JPH0680039B2 - Trifluoromethylketone-substituted peptide derivative, process for producing the same, and therapeutic agent for elastase-mediated tissue degenerative disease containing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION This invention relates to certain trifluoromethylketone substituted peptide derivatives, which are
A human leukocyte elastase (HLE) inhibitor, where such inhibition is desirable, eg in diagnostics in pharmaceutical diagnostics and in related studies, and in tissue-altering diseases of warm-blooded animals such as emphysema, atherosclerosis, It is useful for treating rheumatoid arthritis and osteoarthritis. The invention also relates to a process for its preparation, and a pharmaceutical composition containing this peptide derivative and its use.

The substituted peptides of the present invention have the following formula I:

[0003]

[Chemical 9]

[Wherein n is 1 and R ¹ is ¹ carbon atom]
Is an alkyl group having 5 to 5, A is -CO-, -NH
-CO -, - O-CO- or -S (O ₂₎ - a and, directly B bond or the ^{formula: -NH · CHR 5 · CO ·} NH · CH
R ² · CO— group, wherein R ² is phenyl, benzyl group or may have benzyloxycarbonyl, benzyloxycarbonylamino, phenylsulfonylamino or (phenylsulfonylamino) carbonyl group (C1 -4) alkyl group, R ⁵ is benzyloxycarbonyl or may have a benzyloxycarbonylamino (C1 -4) alkyl group, R ³ the following are: (1) (C1 ~ 4) alkoxy carbonyl, [(C1
~ 4) alkoxycarbonyl] amino, carboxy,
2-[(C1-4) alkoxy] ethoxy, adamantyl, morpholinyl, pyridyl, thienyl, oxopyrrolidinyl, phenyl, [(C1-4) alkoxycarbonyl] phenyl, (carboxy) phenyl, phenoxy, (acetamido) phenoxy , [(C1-4) alkoxycarbonyl] phenoxy, (carbamoylmethyl) phenoxy, benzenesulfonylamino, (methanesulfonylamino) carbonyl, (benzenesulfonylamino) carbonyl, (naphthalenesulfonylamino) carbonyl, (adamantanesulfonylamino) carbonyl Or
(Chlorobenzenesulfonylaminocarbonyl) (C1-6) alkyl group optionally having phenyl; (2) naphthyl, adamantyl, (amino) (chloro)
Phenyl group, hydroxy, (C1-4) alkoxy,
(C1-4) substituted with alkoxycarbonyl, carboxy, halogeno, dihalogeno, acetamide, (methanesulfonylamino) carbonyl, (naphthalenesulfonylamino) carbonyl or [N-benzyl- (4-bromobenzenesulfonyl) amino] carbonyl A phenyl group which may also be; (3) a group of the formula W · SO ₂ · NH · CO · phenyl (wherein W is phenyl optionally having halogeno or nitro); NH. (CH ₂ ) _m- group (where m
Is 2-5, Y is phenyl, benzyl, diphenylmethyl, phenoxymethyl, benzyloxy, (C1-
4) alkoxy, [(C1-4) alkoxycarbonyl] phenylamino, (2-pyridyl) ethoxy or carboxyphenylamino); (5) optionally substituted with (C1-4) alkoxycarbonyl or carboxy. Good cyclopentyl or undecyl group; (6) 2-phenylvinyl group optionally substituted with (C1-4) alkoxycarbonyl, carbonyl or (chlorobenzenesulfonylamino) carbonyl in the phenyl ring; (7) 2- (ureido Carbonyl) vinyl, di (benzyloxymethyl) methyl or di (2-phenoxyethyl) methyl group;] or a pharmaceutically acceptable acid or base addition salt thereof. .

Salts of the compounds of formula I are prepared using pharmaceutically acceptable base- or acid addition salts, ie mineral acids such as hydrochloric acid or organic acids such as citric acid, maleic acid, fumaric acid or acetic acid. Acid addition salts. The base addition salt is
Included are salts prepared using alkali metal hydroxides such as sodium hydroxide, alkali metal carbonates and bicarbonates, alkaline earth hydroxides and organic amine salts. Such salts can be prepared by dissolving the peptide derivative in a mixture of water and a water-miscible organic solvent, adding an aqueous solution of the base and recovering the salt from the aqueous solution.

Advantageous compounds of the present invention have the formula IIa:
And IIc have the S configuration at the chiral center indicated by * (ie the configuration of the naturally occurring L-amino acid). The synthetic methods described below in Methods A and B give diastereomeric mixtures as a result of the presence of products having a compatible configuration of R and S at the chiral center designated by the symbol Δ. . The separation and synthetic methods described below in Methods C and D give largely enantiomerically and diastereomerically pure compounds. Preferred compounds are those that exhibit the S configuration at the center designated by the symbol Δ.

[0007]

[Chemical 10]

The activity of the individual isomers is not the same, as will be appreciated by those skilled in the art, so it is preferred to use the more active isomer. The present invention includes both diastereoisomeric mixtures as well as active S and R isomers.

As will be appreciated by those skilled in the art, trifluoromethyl ketones can exist as solvates, especially hydrates, represented by formulas IIIa and IIIc, which compounds are included in the present invention. It

[0010]

[Chemical 11]

The peptide derivatives of the present invention are commercially available alpha-amino acids (ie, the NH ₂ group is --CO.
It is preferably prepared from an amino acid bound to the carbon atom next to the OH group. For this reason, the preferred R ² and R ⁵ substituents in the above formula of the tetrapeptide derivative are derived from the following amino acids: alanine, valine, norvaline, leucine, isoleucine, norleucine, phenylalanine, aspartic acid, glutamic acid. , Lysine, α-aminobutyric acid and phenylglycine.

The groups of preferred compounds are Examples 10-15 and 3
The compounds listed as the main titles of 8 to 42 are included. Among these compounds, Examples 11, 14 and 39-4
Compound 1 is even more advantageous.

According to another feature of the invention, there is provided a pharmaceutical composition comprising a pharmaceutically effective amount of at least one peptide derivative of formula I and a pharmaceutically acceptable diluent or carrier. To be done.

The compound of formula I can be prepared as follows: Method A The first step is amino alcohol V:

[0015]

[Chemical 12]

(Preferably isolated as the hydrochloride salt). A suitable nitroalkane of the formula R ¹ CH ₂ NO ₂ (prepared by standard methods if not otherwise obtained) and trifluoroacetaldehyde ethyl hemiacetal of the formula [CF ₃ CH (OH) OCH ₂ CH ₃ ]. Henry condensation with Mc
Bee, E .; T. Et al., J. Amer. Chem. So
c. , 78 , 4053 (1956))
I:

[0017]

[Chemical 13]

The nitroalcohol represented by ## STR1 ## is produced, which has two racemic diastereoisomers ([2 (RS), 3 (RS)] and [2 (RS), 3.
(SR)]) (see eg Example Ib). Reduction of the nitro group in compound VI with a suitable reducing agent gives compound V two racemic diastereoisomers ([2 (RS), 3 (RS)] and [2 (R
S), 3 (SR)]) (see eg Example Ic). This amine salt is used directly for the next synthesis.

The second step is a method well known to those skilled in the art, eg M.P. Bodanszky, Principles of Peptide Synthesis (Princi)
plus of Peptide Synthesi
s) [Springer-Ferlag (Berlin, Berlin)
Ringer-Verlag), 1984] and The Peptize Analysis, Synthesis and Biology (The Peptides. Analysis,
Synthesis and Biology) [editor E. Gross of J. Meienhofer, 1
~ Volume 5 (Academic Press in New York), 197
9-1983], compound V
Is a basic intermediate of formulas IVa, IVb and IVc.

[0020]

[Chemical 14]

By using a suitably N-protected cyclic amino acid (eg CBZ-proline), followed by a peptide coupling procedure and appropriate removal of the amino protecting group, a compound of formula IVa is obtained. Removal of similar peptide bonds and protecting groups with the appropriate N-protected dipeptide and tripeptide acids gives compounds of formula IVb and IVc, respectively. Further, the compound of formula IVa can also be converted to the compound of formula IVb or IVc by using the same principle peptide synthesis method. The product obtained as described above is a mixture ([2 (R
S), 3 (RS)] and [2 (RS), 3 (SR)])
Is.

The third step is to convert the intermediate of formula IVa or IVc into a suitable reagent for forming amides, ureas, urethanes and sulfonamides [acid chlorides, anhydrides, mixed anhydrides, isocyanates, 4-nitro]. Carbonates such as phenyl carbonate (Kunz, H. et al., Angew. Ch.
em. Int. Ed. (Eng), 22 , (1983),
, As described on pages 783-784), including chloroformates, sulfonyl chlorides, and sulfinyl chlorides, and then oxidized by methods well known in the literature to convert the intermediates to intermediates. V
IIa and VIIc:

[0023]

[Chemical 15]

It is to change to. The products obtained in this way are mixed ([2 (R
S), 3 (SR)] and [2 (RS), 3 (RS)])
Is.

As will be appreciated by those skilled in the art, the second and third
The order of steps can be changed if appropriate considerations are given regarding the peptide binding method, racemization, protecting group removal method, and the like. Thus, under appropriate conditions, the intermediate of formula VIIIa can be prepared directly from the compound of formula V, or the intermediate of formula VIIc can be prepared directly from the compound of V, IVa or IVc.

The fourth step is to oxidize the intermediate of formula VIIa or VIIc to form product I. A useful method is the use of oxalyl chloride, DMSO and tertiary amines (Marx, M. et al., J. Org. Ch.
em. , 49 (1984), 788-793, best results are obtained with 10-20 equivalents of oxidizing agent), use of acetic anhydride and DMSO, use of chromium trioxide pyridine complex in methylene chloride, And Dess-Martin Periodinane
iodinane) [1,1,1-triacetoxy-
2,1-benzoxiodol-3 (3H) -one] (Dess, DB et al., J. Org. Chem.,
48 (1983), pages 4155-56). The preferred method is the use of Dess-Martin periodinane. The product I obtained by this method, unless separated, consists essentially of a mixture of two diastereoisomers (3 (RS)], corresponding to the center indicated by * in formulas IIa and IIc. The center is generally enantiomerically pure.

The fifth step is the conversion of the product of formula I to other products of formula I, including hydrolysis, coupling and protecting group removal reactions. The stereochemistry of the product mixture is the same as in the fourth step.

Method B This method is an advantageous method over Method A.

The first step is to separate the resulting mixture of racemic diastereoisomers of formula VI by fractional distillation and crystallization to give the nitroalcohol VI to the other, like the product of the first step of Method A. Racemic diastereoisomer of [2 (R
S), 3 (RS)] substantially free of the racemic diastereoisomer [2 (RS), 3 (S)]
R)]. Reduction of the nitro group by an advantageous hydrogenation method with 10% palladium / carbon catalyst gives V as one racemic diastereoisomer [2 (R
S), 3 (SR)]. (It will also be apparent to those skilled in the art that diastereoisomers [2 (RS), 3 (RS)] can also be used to prepare the compounds of the present invention).

The second step is similar to method A, except that
The difference is that the amine V prepared as described in the first step of Method B is used. The product obtained by this method is a substantially pure [2 (RS), 3 (SR)] mixture.

The third step is similar to method A, except that
The difference is that the product produced by the second stage of Method B is used. The product obtained by this method is a substantially pure [2 (RS), 3 (SR)] mixture.

As with Method A, the order of the second and third steps may be changed under suitable conditions.

The fourth step is similar to the fourth step of Method A. The product mixture obtained is the same as the product mixture obtained in the fourth stage of Method A.

The fifth step is the same as the fifth step of Method A.

Method C In this method, for example, all centers corresponding to * and Δ are S
In the case of the products according to IIa and IIc, which is a method for the direct synthesis of the individual (“resolved”) isomers of formula I substantially free from the other diastereoisomer.

The first step involves resolution of the racemate V prepared by the first step of Method B. After releasing the free base corresponding to V, the diastereomeric salt is formed with D-tartaric acid and the salt is separated by fractional crystallization to effect resolution. The base is then liberated from the separated salt, for example 2 (R) 3 (S) in the compound of formula V
The desired amine is obtained by providing the corresponding free base. The product thus obtained is substantially enantiomerically and diastereomerically pure.

The second and third steps are essentially the same as the second and third steps in methods A and B, but with the formula II
Limited to methods that avoid racemization of the centers corresponding to the centers marked with a, IIb and IIc. The product thus obtained is virtually enantiomerically and diastereomerically pure.

The fourth step is limited to the method of avoiding racemization at the centers marked with * and Δ in formulas IIa and IIc. The preferred method is the use of Dess-Martin periodinane. The product I thus obtained is virtually enantiomerically and diastereomerically pure.

The fifth step is limited to a method which avoids racemization at the centers marked * and Δ in formulas IIa and IIc.

Method D A mixture of diastereoisomers (according to the 3 (RS) center) of Formula I prepared by Method A or B is converted to a substantially diastereomerically and enantiomerically pure monomeric form. It is to separate into one isomer. An advantageous way to complete this separation is the use of preparative chromatography, eg MPLC and HPLC.

The second stage is the same as the fifth stage of Method C.

Measurement of Inhibition The potency of the compounds of the invention to act as elastase inhibitors was initially measured by the ability of the compounds of the invention to inhibit the action of human leukocyte elastase (HLE) on low molecular weight peptide substrates. The potency of an inhibitor is evaluated by kinetic measurement of the dissociation constant Ki of the complex formed from the interaction of the inhibitor with HLE. The substrate used is anilide methoxysuccinyl-alanyl-alanyl-
Prolyl-valine-p-nitroanilide [J. Bio
l. Chem. , 254 (1979): 4027-40.
K. on page 32. Nakajima et al .; J. Biol. Ch
em. 257: No. 9 (1982), 5085-5
On page 091, T.S. Described by Teshima et al.]. The HLE enzyme used in these studies was Elastin Products (Elas, St. Louis, Mo., USA).
tin Products) or as described below, Preparative Biochemistry (Preparative Biochemistry).
y), Vol 13, pp. 57-67 (1983).
R. It can also be purified as described by Viscarello et al., Where all work was done in a cold room at 4 ° C.

Salt extraction-DNase treatment:
The starting material, purulent sputum
sputum) was homogenized with 200 ml of cold distilled water and centrifuged at 30,000 x gravity for 20 minutes at 4 ° C. Discard the upper layer and remove the high salt (high salt) from the pellets.
salt) and subjected to extraction using J. Biol. Ch
em. , 252 (1977), pp. 1917-1926. Y. It was treated with DNase by the method of Tsumasi et al. Chromatography on Elastin Agarose: Precipitates from DNase digests were washed with two Tris 50 mM, NaCl 1.0 M (pH 8) 40.
Taken up in a volume of ml. The suspension is centrifuged and the resulting supernatant is dissolved in soluble elastin-sepharose (elast).
in-Sepharose) 4B column (2.5 x 2)
0 cm). Equilibration buffer (Tris 50 mM,
The column was washed with NaCl 50 mM, pH 8.0) until the optical density at 280 nm (OD ₂₈₀ ) of the eluent returned to baseline. Additional contaminating proteins were added to the column volume of 50 mM acetate, 1.0 M NaCl, pH 5.0.
Was used twice to elute. Finally acetic acid 50 mM, NaCl
Elastase and cathepsin G using 1.0M, DMSO 20%, pH 5.0
(HLC-G) was eluted. Fraction 10 collected
The column was developed at 6 ml / min using ml. The active fractions were pooled and 6 l volume of acetate 50 mM, N
Dialyze twice using aCl 0.1M, pH 5.5, Amicon® ultrafiltration device (YM-1).
(0 membrane) to 40 ml.

CM-Chromatography: The concentrated active fraction was previously diluted with acetate 50 mM, NaCl 0.1.
CM-Sephadex® C-50 column (2.M) equilibrated with M, pH 5.5.
2 x 10 cm) and then the column was washed with the above buffer to remove contaminating proteins. Acetic acid 50 mM, N
Continued elution with aCl 0.2 mM, pH 5.5 resulted in Bz-Phe-Val-Arg-pNA.
The peaks of activity assayed for were shifted. Then NaC
Eluted with acetate buffer containing 0.45M, but for the elution of HLC-G, the preparative biochemistry was used.
story), Vol. 9 (1979), pages 15-31. The presence of 1.0 M NaCl in the buffer was required as described by Martodam et al. The column was developed at 30 ml / h using 5.5 ml of collected fractions. From the HLE thus purified, the standard production rate of p-nitroaniline was determined to be 2
Cary 210 spectrophotometer at 5 ° C [Varian Associates
s)]], while automatically acquiring data from
It was measured spectrophotometrically in the visible spectrum of m. The reaction is
10 μl of HLE solution was added to the buffer (sodium phosphate 10 m
M, NaCl 500 mM, pH 7.6) 2.89 ml,
50 μl substrate solution in DMSO and 50 μl DMSO
It was started by pouring into a 3 ml cuvette containing. The initial steady state kinetics of p-nitroaniline formation was calculated by fitting experimental data to a first-order dependence on time by the method of least squares. The rate measured in the absence of inhibitor was used as a standard in the calculation of the inhibitor Ki value.

All peptide derivatives according to the invention are, without exception, "slow-binding" H
It was found to be an LE inhibitor. Therefore, H of the derivative
Special assays were required to accurately measure the Ki value for LE inhibition (for a description of these assays, see Williams, JW and Morrison, JF. , Meth. En
z. 63 (1979), p.437). In a typical experiment, a buffer (sodium phosphate 10 mM, sodium chloride 500 mM, pH, 3 mL cuvette,
7.6) 2.89 ml, 50 μm inhibitor solution in DMSO
1 and 50 μl of substrate solution in DMSO were added. The cuvette was stoppered, inverted several times to mix the contents and kept in a spectrophotometer at 25 ° C. After the reaction solution was thermally equilibrated for 5 minutes, 10 μl of the stock enzyme solution was added to the cuvette to start the reaction. Duplicate or triplicate tests were performed at zero inhibitor concentration and at least three non-zero inhibitor concentrations. Ki values were calculated by the method outlined in the above reference by Williams and Morrison.
The Ki value of the selected compound was less than 10 ⁻⁷ M.

Animal Models Animal models of emphysema include the initiation of progressively progressive destructive lesions of the lung by intratracheal (it) administration of elastic fiber-degrading proteases. Such lesions are usually evaluated for weeks to months after the initial attack. However, the protease causes a clear lesion in the early hours. The early lesions initially bleed, progress to inflammatory lesions by the end of the first 24 hours, and resolve in the first week after the stroke. To take advantage of this initial lesion, the following model was used.

First the hamster was lightly breviated (B
Anesthetize with Revital). Phosphate buffered saline (PBS) at pH 7.4 alone or in saline containing 400 μg of human leukocyte elastase (HLE) is then administered directly into the trachea. After 24 hours the animals are killed, the lungs removed and external tissue carefully trimmed. Following measurement of wet lung weight, lungs are washed with PBS and recovered washable total red and white cells are measured. Wet lung weight values, total lavage red cells and total lavage white cells are dose-dependently increased after administration of HLE. Compounds that are effective elastase inhibitors are able to prevent or reduce severe enzyme-induced lesions, resulting in lower wet weight compared to administration of HLE alone and to the total washed cells (red and white). ) Value is decreased. Use of Compounds to Prevent HLE Lesions To determine induration, compounds can be evaluated by administering the compounds at different times or at different times prior to administration of HLE. The compounds according to the invention resulted in a sufficiently significant reduction in wet lung weight and total lavage cells compared to HLE alone.

The compounds according to the invention showed activity in at least one of the above tests in inhibition measurements or in animal models. Activity of the compound measured as Ki value in inhibition measurement test and HL obtained in animal model test
It should be noted that there is not necessarily a direct correlation between the reduction values of total lavaged cells and wet lung weight compared to administration of E alone. Animal model studies are believed to better predict the activity of the compound in treating emphysema.

Pharmacokinetics : Test compounds are injected intravenously into male Syrian hamsters (80-120 g). The hamsters are lightly anesthetized with ether at varying time periods before and after injection, and approximately 0.2 ml blood samples are taken by cardiac puncture, respectively. Blood is placed in a 2 ml centrifuge tube and allowed to clot for 1 hour. The sample is then centrifuged to remove serum.

The drug level was first set to 5 m for bovine pancreatic trypsin.
It is measured by inactivating the endogenous elastase inhibitor by incubating the same volume of serum for 5 minutes with 50 μl of a buffer containing g / ml. Trypsin-inactivated serum (10 μl) is then added to a 0.52 ml cuvette containing 20 nM buffer for HLE. After holding at a constant temperature for 30 minutes, the substrate (MeOS
uc-Ala-Ala-Pro-Val-pNA, 1.
The reaction is initiated by the addition of 350 μl (6 mm) and the reaction is monitored spectrophotometrically at a wavelength of 410 nM. For comparison, the serum invariance of the test compound is determined as follows: The percent inhibition of serum samples was calculated as follows:

[0051]

[Outer 1]

Where Vo is the rate obtained in the presence of control serum and Vi is the rate of the inhibition reaction. Data are expressed as log inhibition as a function of time after inhibitor administration. From the curve obtained, the approximate serum half-life (t1
/ 2) is calculated.

The compounds according to the invention may be used for the treatment of emphysema, atherosclerosis, osteoarthritis and osteoarthritis conditions, especially in the case of emphysema, warm-blooded animals in need thereof.
In particular, it can be administered to humans. Modes of administration are oral, parenteral, include subcutaneous accumulation by osmotic pump, or by powder or liquid aerosol. The compound is dosed at about 10-250 mg per dose in conventional vehicles, excipients,
With binders, preservatives, stabilizers, flavoring agents or the like as required by an accepted formulation process such as those described in US Pat. No. 3,755,340. It can be blended and formulated in an appropriate dosage form orally or parenterally by a conventional method. For parenteral administration,
About 0.02-10 mg of the compound of the present invention 3 or 4 times a day
1-10 ml of intravenous, intramuscular or subcutaneous injection solution containing / kg body weight is administered. Injectable solutions contain the compounds of the invention in aqueous isotonic sterile solutions or suspensions, optionally with preservatives such as phenol or solubilizing agents such as ethylenediaminetetraacetic acid (EDTA). In the case of powdered aerosols, the compounds of the invention may be used in the Spinhaler® turbo inhaler [Bedford, Mass.
d) Fisons Corporation (Fisons)
Corp. ) Made] 0.1 to 50 m per capsule
In proportion of g, cromolyn sodium (cromolyn
Sodium) can be administered in the same manner, and the average human dose is 1 to 8 capsules daily. Each capsule to be used in a spin Halar contains a pharmaceutically acceptable carrier such as lactose, with the required amount of the compound of the invention remaining in a 20 mg capsule.

In the case of liquid aerosols, the compounds of the invention are administered at a rate of about 100 to 1000 μg per “puff”, ie, the activating release of a standard volume of propellant. Liquid aerosols are administered at a rate of 1-8 puffs per day, varying doses depending on the severity of the condition to be treated, the weight of the patient and the particle size distribution of the aerosol (smaller particles achieve greater lung penetration). To be done. Propellants for liquid aerosols such as fluorinated hydrocarbons or isobutane, vessels, valves and actuators are described by L.S. Latchman (La
chman) and others “The Theory and Practices of Industrial Pharmacy (Th
e Theory and Practicing of
"Industrial Pharmacy""(197)
6) [Published by Lee and Febiger in Philadelphia].

The following abbreviations and idioms are used in the following examples and throughout the specification: atm (atmospheric pressure); bp (boiling point); ° C (degrees Celsius) (all temperatures are in ° C unless otherwise stated). A)); g (gram); hr (hour); mg (milligram); min (minute); ml (milliliter); l (liter); mol (mol); mmol (mmol); mp
(Melting point); N (normative); nm (nanometer); nM
(Nanomoles); satd or sat'd (saturated); aq (aqueous); conc (rich); x (fold);
Room temperature (20-23 °); DCC (1,3-dicyclohexylcarbodiimide); DMF (dimethylformamide); DMSO (dimethylsulfoxide); Et ₂ O (diethyl ether); EtOAc (ethyl acetate); HOAc
(Acetic acid); HOBT (hydroxybenzotriazole); MeOH (methyl alcohol); EtOH (ethyl alcohol); Pd / C (palladium catalyst on charcoal); pNA (paranitroanilide); THF (tetrahydrofuran); CBZ (benzyloxy) Carbonyl); t-BOC (tertiary butyloxycarbonyl); D
MF (dimethylformamide); TEA (triethylamine); DCC (1,3-dicyclohexylcarbodiimide); AcOH (acetic acid); M. (Starting material); N
MM (N-methylmorpholine); ≦ (less than or equal to); TEA (triethylamine); TFA (trifluoroacetic acid); Ac ₂ O (acetic anhydride); CDI (carbonyldiimidazole); WSCDI (water soluble carbodiimide: 1 Ethyl-3- (3-dimethylaminopropyl)
Carbodiimide hydrochloride); DMAP (4-dimethylaminopyridine); Dess-Martin periodinane (Dess-Martin periodinane)
(1,1,1-triacetoxy-2,1-benzoxydol-3 (3H) -one); HCl gas (gaseous HC
l) -otherwise HCl is an aqueous solution; Rh / C
(Rhodium catalyst on charcoal); φ (phenyl group); TLC
(Thin layer chromatography on silica gel unless otherwise specified); Rf (relative mobility in TLC); MP
LC (medium pressure liquid chromatography); HPLC (high pressure liquid chromatography); t _R (HPLC retention time (min)) FR (HPLC flow rate (ml / mi)
n)); Col A [Zorbax (registered trademark) ODS analytical column, 4.6 mm × 25 cm]; C
ol B [Phenomenex (registered trademark) Solvax C-8 analytical column, 4.6 mm × 3
5 cm]; Col C [Altex Ultrasphere: registered trademark]
/ Octyl 10 mmI. D. X 25 cm 5μ analysis and preparative column); flash chromatography (flash column chromatography on silica gel unless otherwise specified); adsorption chromatography (adsorption column chromatography on silica gel). Furthermore, C, H,
Also use N, etc. (the usual symbol for elements): 133.3 Pascal = 1 torr = 14.7 pounds per square inch (psi);
¹ H NMR (nuclear magnetic resonance) spectra were obtained using an 80 MHz or 250 MHz instrument and tetramethylsilane (TMS) as internal standard (special examples of solvents noted); δ (from TMS Ppm moved to low field side; s (single line); d (double line); dd (double line of double line); m (multiple line). Nomenclature: For homogeneity and transparency, the name "amino acid sequence type" is used whenever possible. Also, the amines of formula V and the N-substituents of the C-terminal amides of formulas I, II, III, IV and VII formally derived from V are numbered as shown below:

[0056]

[Chemical 16]

When necessary or, as noted, the various examples were repeated when larger amounts of material were needed.

Example 1 2 (RS), 3 (SR) -3-amino-4-methyl-
1,1,1 trifluoroacetic 2-pentanol hydrochloride salt a. 2-Methyl-1-nitropropane 1-iodo-2-methylpropane (94.0 g, 0.5
1 mol) pre-cooled (0 ° C.) Et ₂ O (180 m)
l) in the AgNO ₂ (100.0 g, was added dropwise to a suspension of 0.65 mol). The reaction was protected from light and stirred overnight allowing it to warm to room temperature. The reaction mixture was filtered through Celite®. The filtrate was concentrated under vacuum and the residue was distilled under vacuum (note potential explosion) to give the product (37.7 g, 0.36).
6 mol); Boiling point 6913.6 Pa (52 mm Hg) and 61-65 degreeC.

B. 2- (RS), 3 (SR) -4-Methyl-3-nitro-1,1,1-trifluoro-2-pentanol 1-Nitro-2-methylpropane from Example 1a (37.
7 g, 0.366 mol), trifluoroacetaldehyde ethyl hemiacetal (58.5 g, 0.366 mol, 90% purity) and K ₂ CO ₃ (3.4g, 0.02
5 mol) and mixed at 60 ° C. for 3 hours and then at room temperature for 3 days. Brine (75 ml) and 1N aqueous H
Cl (50 ml) was added and the lower organic layer was separated. The aqueous layer was extracted with Et ₂ O (2 x 250 ml each) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue on silica gel,
Using gradient eluents of CH ₂ Cl ₂ : hexane (50:50), CH ₂ Cl ₂ : hexane (75:25), CH ₂ Cl ₂ (100%) and MeOH: CH ₂ Cl ₂ (5:95). Purified by flash chromatography, product
Yield (44.9 g): TLC, Rf = 0.65, silica gel, EtOAc: CHCl ₃ (5:95).

C. 2- (RS), 3 (SR) -3-Amino-4-methyl-1,1,1-trifluoro-2-pentanol hydrochloride Et ₂ O (200 ml) A portion of the product of Example 1b in Et ₂ O (200 ml). A solution of (37.0 g, 0.184 mol) in E
A suspension of lithium aluminum hydride (22.0 g, 0.58 mol) in t ₂ O (800 ml) was added dropwise. The reaction mixture was stirred for 45 minutes and a saturated aqueous solution of Na ₂ SO ₄ (110 ml) was carefully added. The resulting suspension was filtered; the filtrate was treated with ethereal HCl and concentrated in vacuo to give the product (37.6 g) used without further purification. ¹ H NMR data (CD ₃ CO
CD ₃ ) (250 MHz): 1.2δ, m, 6H; 2.
3δ, m, 1H; 3.58δ, m, 1H; 4.98δ,
m, 2H; 7.78δ, m, (NH 2).

Example 2 2 (RS), 3 (SR) -N- [3- (4-methyl-
1,1,1 trifluoroacetic 2-hydroxypentyl
)]-L-Prolinamide a. 2 (RS), 3 (SR) -1-[(phenylmethoxy) carbonyl] -N- [3- (4-methyl-1,1,1
1-trifluoro-2-hydroxypentyl)]-L-
Proline-amide A solution of isobutyl chloroformate (11.01 g, 0.08 mol) in anhydrous THF (30 ml) was added to CBZ-L-proline (19.21 g, 0.077 mol) and THF (300 ml). A precooled solution (-15 ° C) of N-methylmorpholine (8.18g, 0.081mol) was added dropwise under a nitrogen atmosphere over 5 minutes. The reaction mixture was stirred at -15 ° C for 15 minutes. The reaction temperature was then reduced to -40 ° C and THF (2
A portion of the product of Example 1c (16.00 g,
0.077 mol) and N-methylmorpholine (8.1
8 g, 0.081 mol) solution was added dropwise to the reaction. The reaction mixture was stirred at −40 ° C. for 1 h, then allowed to warm slowly to room temperature and stirred for an additional 1 h. The reaction product was filtered and concentrated under vacuum. CH the resulting syrup
Dissolved in Cl _3, and washed with aqueous 20% citric acid (2 times in each 75 ml). The organic layer is concentrated under vacuum to give the crude product as a cloudy syrup. The crude product was triturated with ether: hexane (1: 2) to give the product 3 times as a white powder (17.11 g): TLC, Rf =.
0.47, silica gel, MeOH: CHCl ₃ (3: 9
7); mp _{152~154 ℃; HPLC, t R =} 14.
06, 16.63, 18.23, 19.00, Zorbax (registered trademark) ODS analytical column,
H ₂ O: CH ₃ CN (70:30), flow rate 3 ml / mi
n.

B. 2 (RS), 3 (SR) -N- [3-
(4-Methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide The product of Example 2a (2.00 g, 4.97 mmol) was taken up in absolute ethanol (5
0 ml), 10% Pd / c (0.5 g) was added and the reaction mixture was hydrolyzed (310) at room temperature for 3 hours.
126.53Pa, 3.15kg / cm ² (45ps
i)). The reaction mixture was filtered through Celite and the solvent removed under vacuum to give the product (1.36 g) used without further purification.

Example 3 2- (RS), 3 (SR) -L-valyl-N- [3-
(4-methyl-1,1,1 -trifluoro-2-hydro
Xypentyl)]-L-prolinamide a. N-[(phenylmethoxy) carbonyl] -L-valyl-L-proline methyl ester 1-hydroxybenzotriazole (163.3 g, 1.2 mol) was precooled (0.
C.), a solution of N-benzyloxycarbonyl-L-valine (151.8 g, 0.6 mol) in DMF (1.3 l) was added and stirred for 15 minutes. L-proline methyl ester hydrochloride in DMF (0.7 l) (100.0 g,
0.6 mol) and TEA (64.2 g, 0.63 mol) suspension was added, followed by 137.1 g DCC,
0.66 mol) was added. The reaction mixture was stirred at 0 ° C. for 3 hours and then at room temperature for 3 days. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was washed with EtOAc (0.
75 l) and filtered. The filtrate subsequently 20% aqueous citric acid (0.75 l), washed with saturated aqueous NaHCO ₃ and brine. The organic phase is dried over MgSO ₄ , filtered and concentrated under vacuum to give the crude product (271.3 g).
Occurred. On the product on silica gel, starting with _{CH 2 Cl 2, MeOH: CH} 2 Cl 2 and purified by flash chromatography using a gradient elution ending with (four ninety-six) to give the product (218.1 g) TLC, Rf =
0.48, silica gel, MeOH: CHCl ₃ (5: 9
5).

B. N-[(phenylmethoxy) carbonyl] -L-valyl-L-proline MeOH (1.6 l)
Part of the product of Example 3a (158.8 g, 0.438
Mol) was added 1N aqueous NaOH (500 ml) and the solution was stirred at room temperature for 17 hours. 1N aqueous NaOH
(100 ml) was added and the mixture was continuously stirred for 5 hours. Additional 1N aqueous NaOH (50 ml) was added and stirred overnight. The reaction product was concentrated under vacuum to remove MeOH. H ₂ O (1.0 l) was added and the aqueous solution was diluted with Et ₂ O.
It was extracted with. The aqueous solution was acidified with 1N aqueous HCl (700 ml) and extracted with EtOAc. The EtOAc extract was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the product (159.2 g); TL
C, Rf = 0.34, silica gel, MeOH: CHCl
₃ : AcOH (5: 94: 1).

C. 2- (RS), 3 (SR)-[(phenylmethoxy) carbonyl] -L-valyl-N- [3-
(4-Methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide isobutyl chloroformate (77.3 g, 0.566 mol) was added to anhydrous T
N-methylmorpholine (59.2) in HF (2.5 l)
5 g, 0.566 mol) and the product of Example 3b (19
7.2 g, 0.566 mol) of precooled (-15
(° C.) Solution and the reaction mixture was stirred for 10 minutes. The temperature was lowered to -40 ° C and N-methylmorpholine (59.
25 g, 0.566 mol) was added, followed by THF.
The product of Example 1c) in 11 (2.5 l) (117.5 g,
0.566 mol) solution was added dropwise. The reaction product was allowed to warm to room temperature and stirred for 3 days. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was dissolved in EtOAc and subsequently washed with H ₂ O, 1N aqueous HCl and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give crude product (267.8 g). The product on silica gel from THF: toluene (5:95) to THF:
Purified by flash chromatography using a gradient eluent of toluene (25:75) to give the product (183.8
g) was obtained; TLC, Rf = 0.4, silica gel, TH
F: Toluene (20:80).

D. 2 (RS), 3 (SR) -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide EtOH (0.61) Part of the product of Example 3c (3
6.7 g, 0.073 mol) and 10% Pd / c (1
Mix the mixture of 0% and 50% water content) with a pearl shaker (Pa
rr shaker) (303.924 Pa, 3 atm
Hydrogenated with H ₂ ). After 1 hour, depressurize the reaction vessel,
Repressurized with H ₂ . After an additional 0.5 h, the reaction mixture was filtered through Celite and concentrated under vacuum to give the product (2
6.0 g) was obtained; TLC, Rf = 0.16, silica gel, MeOH: CHCl ₃ (5:95).

Example 4 2- (RS), 3 (SR) -3-amino-4-methyl-
1,1,1-trifleOro-2-pentanol hydrochloride
a. 2-Methyl-1-nitropropane of the compound of Example 1a
An alternative method for manufacturing is as follows.

A 5 liter, 3-neck round bottom flask was equipped with a mechanical stirrer, thermometer, dropping funnel and N ₂ inlet.
The flask was charged with AgNO ₂ (100 liters) in Et ₂ O (2.5 l).
6.8, 6.54 mol) were charged and isobutyl iodide (927.2 g, 5.03 mol) was placed in the dropping funnel. Both the flask and the dropping funnel were covered with an aluminum sheet to protect the reaction from light. After cooling the stirred suspension to about 5 ° C. (ice bath), iodide addition was started over 2 hours. The reaction temperature is 5 ° C during the addition process.
Or kept below that. At the end of the addition, the reaction vessel was packed in ice and allowed to slowly warm to room temperature overnight.
Some NMR analysis taken from the reaction mixture after 48 hours of stirring showed that all of the isobutyl iodide had been consumed. The reaction mixture was filtered through Celite to remove silver salts and the filter cake was washed with Et ₂ O (3 x 500 ml).
The combined filtrate was dried over MgSO ₄ , filtered and concentrated on a rotary evaporator (bath temp = 35 ° C.) to about 600 ml. Fractional distillation (atmospheric pressure) (being careful of potential explosion hazard) gave the purified nitro nitrogen compound (350.4 g, 68% yield); bp 135-142 ° C.

B. 2 (RS), 3 (SR) -4-methyl-3-nitro-1,1,1-trifluoro-2-pentanol mechanical stirrer, 3 l equipped with N ₂ inlet, three neck round bottom flask. K ₂ CO ₃ (470.0 g, 3.4 mol) Example 4
Charge the product of a (350.0 g, 3.4 mol) and finally trifluoroacetaldehyde ethyl hemiacetal (708.0 g, 4.4 mol). The mixture was vigorously stirred at room temperature for 76 hours, at which time ¹ H-NMR showed almost complete consumption of the nitroalkane. The reaction mixture is C
Diluted with H ₂ Cl ₂ and filtered. PH of the filtrate with aqueous HCl
= 3 was processed. Separate the layers and separate the aqueous layer with CH ₂ Cl.
_It was washed with ₂ (500 ml). The bound CH ₂ Cl ₂ fraction was washed with H ₂ O (1 L) and brine (1 L). Dry (MgSO ₄ ) and concentrate to give crude product 8 as a yellow oil.
This yielded 54.6 g. ¹ H-NMR shows the two diastereomeric nitroalcohols (present in a ratio of about 3: 1 calculated by integration of alcohol protons), which is acetone-d ₆ contaminated by small amounts of solvent and starting materials. When carried out in, it appears consistently in the range δ 6.0-6.5.

Distillation at reduced pressure yielded the following fractions: Weight Boiling point (° C) A 191.7 g 42-50 ° C / atm S. M. + Solvent B 34.8 g 35 ° / 1 torr to 45 ° /. 5 Torr C 213.6 g 45 ° /. 5 Torr to 95 ° / 1.5 Torr D 337.8g 95 ° / 1.5 Torr to 105 ° / 2 Torr E 114.0g Trap Volatiles At this point to facilitate purification in subsequent synthetic steps. At this point, efforts were made to obtain one pair of the major diastereomers in a substantially pure state and to advance only this material.
The major diastereomeric pair crystallizes from a mixture of diastereomers, also cold pentane, giving colorless needles. Fraction C from the above distillation was thus allowed to crystallize overnight in the refrigerator. The product was collected, washed with cold pentane, dried in a vacuum oven for several hours (note that this material is somewhat volatile and a significant amount can be lost under extended vacuum processing), Pure substance 5
Yield 2.0 g. Fractions known to contain significant amounts of the desired isomer (by NMR) were repeatedly processed in this manner (and to provide new fractions that were more enriched in the desired diastereomer). Redistilled into), resulting in a total of substantially pure nitroalcohol of 19
7.7 g are obtained. This quantity represents a typical type of process carried out, but does not represent an upper yield limit.

C. 2 (RS), 3 (SR) -3-amino-4-methyl-1,1,1-trifluoro-2-pentanol hydrochloride anhydrous EtOH (232 ml) was added to 10% Pd.
/ C catalyst (2.30 g) was added under N ₂ (*). The product of Example 4b (22.93 g, 0.144 mol) was added and the resulting mixture was mixed with a Parr hydrogenator (approx. 480000 Pa, 3 kg / cm ² (55 psi)).
H ₂ ) overnight. The catalyst was removed by filtration through Celite. The filter cake was then washed with EtOH. HC
It was bubbled through the filtrate combined with 1 gas until about 8 g (about 0.22 mol) had been adsorbed. The solution was concentrated on a rotary evaporator and the resulting residue was concentrated several times from Et ₂ O to give a white solid. The solid was washed with Et ₂ O and dried in a vacuum oven overnight to give 20.79 g (88%) of amine hydrochloride. Due to its melting point, the material is 90% when heated slowly.
It softens at ℃ and melts at 118-120 ℃. 110 samples
When submerged in a bath preheated to ° C, it dissolved immediately.

* Slightly less active catalyst (eg 10
% Pd / BaSO ₄ , wet 10% Pd / c) or insufficient reaction time leads to the formation of one or several by-products.

Example 5 2 (RS), 3 (SR) -L-valyl-N- [3- (4
-Methyl-1,1,1 -trifluoro-2-hydroxy
Pentyl)]-L-prolinamide a. CB in N-[(phenylmethoxy) carbonyl-L-valyl-L-proline methyl ester DMF (11, dried on sieve)
A solution of ZL-valine (100.0 g, 0.40 mol) was equipped with a mechanical stirrer, N ₂ inlet and thermometer 3
l, added to a 3-necked round bottom flask. The reaction product was cooled to 0 ° C. and HOBT hydrate (108.1 g, 0.80 mol)
Was added. L-proline methyl ester hydrochloride (6
6.2 g, 0.40 mol) and TEA (41.8 g,
0.42 mol of DMF (500 ml) slurry was allowed to stir for about 15 minutes before being added in one portion. DMF (500 ml) additionally to complete the transportation of the slurry
It was used. DOC (90.8 g, 0.44 mol) was added to the reaction and rinsed with DMF (100 ml). The reaction product was stirred at 0 ° C. for 3 hours, then warmed to room temperature and
Allowed to stir for days. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. The filter cake was washed with EtOAc (3 × 1 l) and the resulting filtrate was concentrated to give material combined with residue from concentration of DMF solution. The combined product mixture (about 2.5 l) was diluted with Et ₂ O (2 l),
Stored in refrigerator overnight. The precipitate was removed by filtration. The filtrate was washed with 1N HCl (1 l) and an additional precipitate formed and was removed by filtration. The filtrate is then 1N
HCl (1 l), H ₂ O (0.5 l), saturated NaHC
Wash with O ₃ (2 × 1 l) and brine (0.5 l). Dry (MgSO ₄ ) and concentrate to give the crude product 58.
It gave 7.2 g. This material is treated with silica gel (3.5k
g) top gradient eluent (CH ₂ Cl ₂ to 5% MeOH: C
Flash chromatography with H ₂ Cl ₂ (5:95)). The combined fractions were repeatedly chromatographed to remove impurities. The combination of fractions containing the desired product yielded 500.7 g (87%) of material contaminated with small amounts of low Rf impurity; TL
C, Rf = 0.37, silica gel, Et ₂ O: hexane (3: 1); Rf = 0.53, silica gel, MeOH:
CHCl ₃ (5:95).

B. N-[(phenylmethoxy) carbonyl] -L-valyl-L-proline Product of Example 5a (50
A solution of 0.7 g, 1.38 mol) in methanol (4 l) was added to a 12 l, 3-neck round bottom flask equipped with a mechanical stirrer and N ₂ inlet. 1N NaOH for stirring solution
(1.4 l) is added to bring the pH to about 13. After stirring the reaction mixture for 3 hours, the pH dropped to 11. An additional 1N NaOH (0.1 l) was used to bring the pH to 12, and the reaction product was stirred at room temperature overnight. MeOH was removed from the reaction mixture by concentrating on a rotary evaporator. During the solvent removal step, 1 liter of H ₂ O was added to reduce the concentration of the base. The aqueous solution was washed with Et ₂ O and then acidified with 1N HCl (1.51) to a pH of about 3.5. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 11). The combined organics were washed with brine (1l), dried (MgSO _4), to give the product 493.0g (100%) and concentrated to a white solid; TLC, R
f = 0.51, silica gel, MeOH: CHCl
_{3 With addition of} (5:95) AcOH.

C. 2- (RS), 3 (SR)-[(phenylmethoxy) carbonyl] -L-valyl-N- [3-
(4-Methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide The product of Example 5b (105.3 g, 0.302 mol) was added to N
₂ under anhydrous THF in a 3 l three-necked round bottom flask equipped with mechanical stirrer, thermometer, N ₂ inlet and dropping funnel.
It was dissolved in (1.5 l). The solution was cooled to -35 ° C, N
Treated with 1 equivalent of MM (34 ml, 0.309 mol). Isobutyl chloroformate (39 ml, 0.307 mol) was added dropwise over 20 minutes while maintaining the temperature at ≤-35 ° C. After the addition is complete, the reaction mixture is cooled to -35 ° C.
It was stirred for 1 hour. NMM 1 equivalent (34 ml)
Was added. The product of Example 4c (62.8 g, 0.302 mol) in THF (300 ml) was then added at a temperature <-.
It was added at a rate such that it was maintained at 35 ° C. After the addition was complete, the temperature was maintained at ≤-35 ° C for 1 hour, after which the mixture was allowed to warm to room temperature with stirring overnight. The reaction mixture was filtered and the filter cake was washed with THF (1 l). The collected filtrate was concentrated to obtain 189 g of a crude product. This material was loaded onto silica gel (5000 ml) with THF: toluene (1:
Flash chromatography, eluting with 9). Once the product started to elute, the solvent polarity changed in a gradient: THF: toluene (15:85); TH
F: Toluene (20:80) and finally MeOH: T
HF: toluene (2.5: 30: 70) (MeOH usage was minimized to prevent elution of impurities with low Rf values). Concentration of the column fractions followed by drying under vacuum overnight yielded 12.0 g (8%) of slightly impure product and 131.6 g (87%) of substantially pure material. (Caution: A solution of this material, when thoroughly dried, resulted in a foam that finally solidified under extended vacuum treatment. Be careful to do so).
TLC, Rf = 0.25, silica gel, MeOH: CH
Cl ₃ (5:95); Rf = 0.37, silica gel, T
HF: Toluene (20:80). On slight instillation of the material, the two isomers resolved to give a spot with Rf = 0.37 and Rf = 0.46, silica gel, TH
F: Toluene (20:80).

(Caution: Maintaining the internal temperature quoted in this way seems to be difficult to obtain a substantially pure product).

D. Formation of 2- (RS), 3- (SR) -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolineamide Example 5c (131.6 g, 0.262 mol) in EtOH (750 ml) and in a large Parr hydrogenation bottle under N ₂ 10% Pd / c catalyst (50% H ₂ O, 13.0 g). ) Combined with. The reaction mixture was 480.000 Pa, H ₂ 3.85 kg / cm (5
Shake on Parr apparatus under 5 psi). Repressurization with H ₂ was continued until no further absorption was observed. T
Examination of the reaction by LC showed complete consumption of starting material. The reaction mixture was filtered through Celite and concentrated to foam. This material was triturated with Et ₂ O, filtered and dried to give 81.4 g (84%) of a light gray solid; TL
C, Rf = 0.41, silica gel, CHCl ₃ : MeO
H (10: 1).

[0078] Example 6 1- [2- (tricyclo [3.3.1.1 ^{3 '7]} deci -
1-yl) ethoxycarbonyl] -N- [3 (RS)-
3- (4-methyl-1,1,1-trifluoro- 2-o
Xoxopentyl)]-L-prolinamide a. 4-nitrophenyl 2- [tricyclo (3.3.1.1 ^{3 '7)} Desi-1-yl] - ethyl carbonate Et ₂ O (25ml) solution of p- nitrophenyl chloroformate (1.17 g, 5.82 mmol) solution at 0 ° C
Pyridine (5 ml) was added at, followed by Et ₂ O (20 ml).
2- (1-adamantyl) ethanol (1.
00 g, 5.54 mmol) was added dropwise over 1 hour. The resulting mixture was stirred for 12 hours at room temperature, and partitioned between H ₂ O and Et ₂ O. The ethereal layer with 5% aqueous HCl,
Washed with pH 7.0 phosphate buffer, dried over MgSO ₄ , filtered and the solvent removed under vacuum. The crude product was purified by flash chromatography on silica gel, eluting with EtOAc: hexane (5:95) to give the product (1.10 g) as a white powder;
TLC, Rf = 0.29, silica gel, EtOAc: hexane (5:95).

B. 1- [2- (tricyclo [3.3.
1.1 ^{3 '7]} deci-1-yl) ethoxycarbonyl] -
N- [2 (RS), 3 (SR) -3- (4-methyl-
1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide DMF (50 ml) product of Example 6a (731.0 mg, 2.98 mmol), product using the method of Example 2b. A solution of (500 mg, 1.80 mmol) and K ₂ CO ₃ (2.57 g, 18.6 mmol) was stirred at room temperature for 18 hours, filtered and the solvent removed under vacuum. The residue was taken up in EtOAc and 10% aqueous Na
Washing with OH three times, solid K ₂ CO ₃ : Na ₂ SO ₄ (1
0:90), filtered and the solvent removed under reduced pressure. Crude product on silica gel MeOH: CHCl
Chromatography eluting with ₃ (1:99). The resulting solid was washed with hexanes to give the product as a white solid (340 mg); HPLC, t
_R = 5.86, 6.38, Turubax (Zorba
x: ODS analytical column, flow rate = 2 ml / mi
n, CH ₃ CN: H ₂ O: TFA (70: 30: 0.
1).

C. 1- [2- (tricyclo [3.3.
1.1 ^{3 '7]} deci-1-yl) ethoxycarbonyl] -
N-3 (RS)-[3- (4-Methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide-in dry CH ₂ Cl ₂ (15 ml) cooled to 43 ° C. To a solution of oxalyl chloride (1.09 g, 8.60 mmol) in DMSO (1..mM) in dry CH ₂ Cl ₂ (10 ml).
37 g, 17.3 mmol) was added dropwise over 15 minutes. The solution was stirred for 10 minutes and the product of Example 6b (340 mg, 0.72 mmol) was added in a similar manner over 30 minutes. After stirring the solution at −43 ° C. for another hour, TEA (4.80 ml, 34.5 mmol).
Was slowly added and the solution was allowed to warm slowly to room temperature and stirred for 2 hours. Dilute the solution with CH ₂ Cl ₂ and
% Aqueous HCl, 5% aqueous NaOCl, solid K ₂
Dry over CO ₃ : Na ₂ SO ₄ (10:90), filter and remove the solvent under vacuum. The crude product was purified by two successive flash chromatography on silica gel eluting with MeOH: CHCl ₃ (0.1: 99.9) and EtOAc: hexane (1: 5) to give the product (130 mg) as a white solid. Obtained: TLC, Rf = 0.5
0, silica gel, MeOH: CHCl ₃ (5:95);
HPLC, t _R = 5.31, Tuolvacs ODS analytical column, flow rate 2 ml / min, CH ₃ CN: H ₂ O: TF.
A (70: 30: 0.01).

Calculated value: C ₂₄ H ₃₅ N ₂ F ₃ O ₄ .0.25H ₂ O: C, 60.43; H, 7.50; N, 5.87 Measured value: C, 60.50; H , 7.45; N, 5.74 Example 73 3 (RS) -1- (4-phenylbutylcarbonyl)-
N- [3- (4- methylation trifluoro -
2-oxopentyl)]-L-prolinamide a. Two
(RS), 3 (SR) -1- (4-phenylbutylcarbonyl) -N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide THF A solution of 5-phenylvaleric acid (0.330 g, 1.86 mmol) and N-methylmorpholine (0.280 g, 2.79 mmol) in (100 ml)-
Cooled to 15 ° C. A solution of isobutyl chloroformate (0.280 g, 2.05 mmol) in THF (5 ml) was added dropwise and the mixture was stirred at -15 ° C for 10 minutes, then the temperature was reduced to -40 ° C and THF (25 ml). ) In example 2
The product (0.500 g, 1.
86 mmol) solution was added dropwise. Mix at -40 ° C for 1
Stir at room temperature and room temperature overnight. The mixture was filtered and the filtrate was concentrated under vacuum. The crude product on silica gel, Me
Purification by flash chromatography eluting with OH: CHCl ₃ (3:97) gave the product (0.60 g) as a white solid; TLC, Rf = 0.4.
0-0.51, silica gel, MeOH: CHCl
₃ (3:97).

B. 3 (RS) -1- (4-phenylbutylcarbonyl) -N- [3- (4-methyl-1,1,1)
-Trifluoro-2-oxopentyl)]-L-prolinamide DMSO in dry CH ₂ Cl ₂ (80 ml)
A solution of (4.22 g, 54.0 mmol) was pre-cooled (−60 ° C.) under a nitrogen atmosphere, CH ₂ Cl ₂ (10 mmol).
To a stirred solution of oxalyl chloride (3.43 g, 27.0 mmol) in 1) was added dropwise over 10 minutes. The temperature never exceeded -55 ° C during the addition. Mixture-6
Stir for 15 minutes at 0 ° C. and add a solution of the product of Example 7a (0.580 g, 1.35 mmol) in CH ₂ Cl ₂ (100 ml) dropwise at −60 ° C. over 10 minutes. The reaction mixture was stirred at -60 ° C for 1 hour. Diisopropylethylamine (6.98 g, 54.0 mmol) at -60 ° C for 1
It was added dropwise over 0 minutes. The reaction mixture was stirred for 1 hour while warming to room temperature. The reaction mixture is subsequently treated with 1N aqueous H
Wash twice with Cl and brine and concentrate under vacuum to give the crude product as an orange syrup (0.85 g). The crude product was loaded onto silica gel 1) MeOH each:
CHCl ₃ (3:97), 2) MeOH: CHCl
₃ (3:97) and 3) Et ₂ O: hexane (90: 1
Purified by tri-sequential flash chromatography, eluting with 0) to give the product as a white foam (319 m
g) was obtained; TLC, Rf = 0.33~0.40, silica gel, Et ₂ O: hexane (90:10); HPL
C, t _R = 17.93, 18.55, Tourvacs O
DS analytical _{column, H 2 O: CH 3 CN} (55:45), flow rate = 2 ml / min.

Calculated: C ₂₂ H ₂₉ N ₂ O ₃ F ₃ 1.25H ₂ O: C, 58.85; H, 7.07; N, 6.24 Measured value: C, 58.91; H , 6.83; N, 6.13 Example 83 (RS) -1-[(phenylmethoxy) carbonyl]
-N-[3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-Purorin'ami de dimethyl sulfoxide (0.890 g, 11.4 m mol) Oyopi anhydrous methylene chloride ( 5 ml) solution of -60
Oxalyl chloride (0.75 g, 5.9 mmol) and anhydrous methylene chloride (5 ml) were added dropwise under nitrogen at ° C to a stirred solution. The reaction mixture was allowed to warm to -25 ° C, after which a solution of the product prepared using the method of Example 2a (0.200 g, 0.947 mmol) and anhydrous methylene chloride (5 ml) were added. The resulting mixture is -25 ° C.
It was stirred for 0.5 hour. Triethylamine (1.94
g, 19.2 mmol) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was filtered. The filtrate was evaporated. The residue was dissolved in chloroform. The chloroform solution was washed successively with 1N aqueous HCl, then brine,
Dry over a ₂ SO ₄ . The solvent was removed under vacuum to give a crude product (0.147g). The crude product on silica gel,
Purification by flash chromatography eluting with CHCl ₃ : MeOH (97: 3) gave the product (0.
11g); TLC, Rf = 0.25 , CHCl 3: Et
OAc (90:10).

Calculated value: C ₁₉ H ₂₃ F ₃ N ₂ O ₄ .1.5H ₂ O: C, 53.39; H, 6.13; N, 6.55 Measured value: C, 53.55; H , 5.78; N, 6.56 Example 9 2 (RS), 3 (SR) -L-valyl-N- [3- (4
-Methyl-1,1,1 -trifluoro-2-hydroxy
Pentyl)]-L-prolinamide a. N-[(phenylmethoxy) carbonyl] -L-valyl-L-proline methyl ester The method of Example 3a was repeated.

B. N-[(phenylmethoxy) carbonyl] -L-valyl-L-proline The procedure of Example 3b was followed by the procedure of Example 9a.
Was repeated with the above material.

C. 2-Methyl-1-nitropropane The method of Example 1a was repeated.

D. 2 (RS), 3 (SR) -4-Methyl-3-nitro-1,1,1-trifluoro-2-pentanol The method of Example 1b was repeated using the material from Example 9c.

E. 2 (RS), 3 (SR) -3-Amino-4-methyl-1,1,1-trifluoro-2-pentanol hydrochloride The method of Example 1c was repeated using the material from Example 9d.

F. 2 (RS), 3 (SR)-[(phenylmethoxy) carbonyl] -L-valyl-N- [3-
(4-Methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide The method of Example 3c was repeated using the compounds from Examples 9a and 9e.

G. 2 (RS), 3 (SR) -L-Valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide Exemplifies the method of Example 3d Repeated with compound from 9f.

Example 10 3 (RS)-[2- (methoxycarbonyl) ethylcarbonyl] -L-norleucyl-L-valyl-N- [3-
(4-methyl-1,1,1-trifluoro-2 -oxo
Pentyl)]-L-prolinamide a. A solution of N- [2- (methoxycarbonyl) ethylcarbonyl] -L-norleucine 1N sodium hydroxide (100 ml, 100
(mmol) was added dropwise at 0 ° C. under nitrogen to a vigorously stirred mixture of L-norleucosine (6.55 g, 50 mmol) and methylene chloride (250 ml). 3-carbomethoxypropionyl chloride (7.52 g, 50 mmol)
Was added dropwise. The resulting reaction mixture was stirred at 0 ° C. for 15 minutes. The cooling bath was removed and water (100 ml) was added. p
H was adjusted to 1 with 3N aqueous HCl. Ethyl acetate (20
0 ml) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with brine, Na ₂
Dried over SO ₄ . The solution was filtered. The solvent was removed under vacuum to give the crude product (10.73 g). A portion of the crude product (6.47 g, 26.4 mmol) was purified by flash chromatography on silica gel with CHCl ₃ : MeOH (97: 3) to give the product (5.3
1 g) was obtained; TLC, R _f -0.45, silica gel,
CHCl ₃ : MeOH: AcOH (95: 4.75:
0.25).

B. 2 (RS), 3 (SR)-[2- (methoxycarbonyl) ethylcarbonyl] -L-norleucyl-L-valyl-N- [3- (4-methyl-1,1,)
1-trifluoro-2-hydroxypentyl)]-L-
Proline amide dicyclohexylcarbodiimide (3.
46 g, 16.8 m) in THF (70 ml) Example 3d
Product (5.60 g, 15.3 g) produced using the method of
(mmol) The product of Example 10a (3.75 g, 15.3 mmol) and 1-hydroxybenzotriazole (4.1
3 g, 30.6 mmol) was added to the precooled (0 ° C.) solution. The resulting solution was gradually warmed to room temperature and allowed to stir overnight. The reaction product was filtered and concentrated under vacuum. The residue was diluted with EtOAc and the resulting solution was washed with saturated aqueous NaHCO ₃ and brine, Na ₂ SO ₄
Dried above, filtered and concentrated in vacuo to give crude product. The product was loaded onto a silica gel column with Et ₂ as eluent.
O (100%), Et ₂ O: EtOAc (90: 1
0), Et ₂ O: EtOAc (75:25), Et ₂ O:
Purify by flash chromatography using a gradient of EtOAc (50:50) to give the product (5.6 g).
Was obtained; TLC, _Rf- 0.45, silica gel, MeO.
_{H: CHCl 3 (1: 9} ).

C. 3 (RS)-[2- (methoxycarbonyl) ethylcarbonyl] -L-norleucyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)]- DMSO (27.0 ml) in L-prolinamide CH ₂ Cl ₂ (27 ml).
A solution of 0.378 mol) was slowly added to a precooled (-65 ° C) solution of oxalyl chloride (16.5 ml, 0.189 mol) in CH ₂ Cl ₂ (350 ml). The resulting solution was stirred for 15 minutes and CH ₂ Cl ₂ (250 ml)
A solution of the product of Example 10b (5.60 g, 0.00943 mol) in was added. The reaction product was stirred at −65 ° C. for 1 hour and diisopropylethylamine (67.0 ml,
0.378 mol) was added dropwise. The reaction product was allowed to warm to room temperature, then washed with 1N aq. HCl and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product. The crude product on a silica gel column,
Et ₂ O (100%), Et ₂ O: EtOAc (50: 5
0), purified by flash chromatography eluting with a gradient of EtOAc (100%) to give a partially purified product which was further purified on silica gel,
CHCl ₃ (100%), MeOH: CHCl ₃ (2.
5: 97.5) and MeOH: CHCl ₃ (5: 9
Flash chromatography eluting with 5) - was further purified by, gave the final product _{(3.24g); HPLC, t R} = 6.80 and 12.98, Tsuorubakkusu ODS analytical column, H ₂ O: CH ₃ CN (6
5:35), flow rate = 2 ml / min.

Example 11 3 (RS)-[(2-carboxyethyl) carbonyl]
-L- norleucyl -L- valyl -N- [3- (4-methyl-1,1,1-trifluoro-2-oxo-pentyl
)]-L-Prolinamide 1N aqueous NaOH (9.5
ml) was added to a solution of the product of example 10c (2.60 g, 4.39 mmol) in MeOH (95 ml). The reaction product was stirred at room temperature overnight, 1N aqueous HC
1 (10.5 ml) was added. The reaction product was concentrated under vacuum and H ₂ O (35 ml) was added. Et the suspension
It was extracted with OAc, the organic layer was washed with brine, Ha ₂ SO ₄
Dry over, filter, and concentrate under vacuum to give the product (2.1
g) was obtained. HPLC, t _R = 12.63 and 19.
05, Tuolvacs ODS analytical column, H ₂ O: CH ₃
CN (65:35), flow rate = 0.5 ml / min.

Example 12 3 (RS)-[(phenylmethoxy) carbonyl] -L
-Α-glutamyl-L-valyl-N- [3- (4-methyl
Le-1,1,1-trifluoro-2-oxopePunch
)]-L-Prolinamide phenyl methyl ester
a. 3 (RS), 3 (SR)-[(phenylmethoxy)
Carbonyl] -L-α-glutamyl-L-valyl-N-
[3- (4-methyl-1,1,1-trifluoro-2-
Hydroxypentyl)]-L-prolinamide phenyl
Methyl ester isobutyl chloroformate (0.53
ml (4.1 mmol) N-base in THF (30 ml).
Nyloxycarbonyl-L-glutamic acid-α-ben
Dil ester (1.52 g, 4.1 mmol) and N-
Preparation of methylmorpholine (0.45 ml, 4.1 mmol)
Add to precooled (-15 ° C) solution. Reaction mixture
Was stirred for 10 minutes and then cooled to -40 ° C. THF
The product of Example 3d (1.5 g, 4.1 m) in (30 ml)
Mol) solution and the reaction product is stirred overnight and slowly added.
Each was allowed to warm to room temperature. The reaction product is filtered,
Concentrated under vacuum. The residue was taken up in EtOAc and 1N water
Washed with neutral HCl and brine, Na₂SO_FourDried on
, Filtered and concentrated to give crude product. Crude product
CHCl as the eluent on the Kagel column₃(100
%), MeOH: CHCl₃(2.5: 97.5) and
And MeOH: CHCl₃Use (5:95) gradient
Purified by flash chromatography to give the product
(2.13 g) was obtained; TLC, R_f= 0.43, Siri
Kagel, MeOH: CHCl₃(5:95).

B. 3 (RS)-[(phenylmethoxy)
Carbonyl] -L-α-glutamyl-L-valyl-N-
[3- (4-methyl-1,1,1-trifluoro-2-
Oxopentyl)]-L-prolinamide phenylmethyl ester DMSO (8.4 ml) in CH ₂ Cl ₂ (8 ml).
0 ml, 0.118 mol) carefully with CH ₂ C
Oxalyl chloride (5.2 ml, l ₂ (100 ml)
0.059 mol) to a precooled (-65 ° C) solution. The solution was stirred for 15 minutes and CH ₂ Cl ₂ (100
The product of Example 12a (2.13 g, 2.96 m) in
Mol) solution was added dropwise. The reaction product was stirred at −60 ° C. for 1 hour, and N, N-diisopropylethylamine (2
0.9 ml, 0.118 mol) was added dropwise. The reaction product was allowed to warm to room temperature, washed with 1N aqueous HCl and brine, filtered and concentrated to give crude product. The product was partially loaded on a silica gel column with Et ₂ O as eluent.
It was purified by - flash chromatography using a gradient solution of EtOAc (50:50) and EtOAc (100%): (100 %), Et 2 O. The product was finally loaded onto a silica gel column with CHCl ₃ (100
%), MeOH: CHCl ₃ (1:99), MeOH:
CHCl ₃ (2:98), MeOH: CHCl ₃ (3: 9
Purification by flash chromatography using 7) and MeOH: CHCl ₃ (5:95) step gradient to give product (1.35 g); HPLC, t _R =
7.2 and 11.5, Tsuorubakkusu ODS analytical _{column, H 2 O: CH 3 CN} (50:50), flow rate = 2 ml /
min.

[0097] Example 13 3 (RS) -N ² - [2- (methoxycarbonyl) ethyl carbonyl] -N ⁶ - [(phenylmethoxy) carbonyl] -L- lysyl -L- valyl -N- [3- ( 4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-proline N'amido a. N ² - [(2-methoxycarbonyl) ethyl carbonyl] -N ⁶ - phenyl -
Methoxycarbonyl lysine 1N aqueous NaOH (3 ml)
Was added to a precooled (0 ° C.) solution of N-benzyloxycarbonyl-L-lysine (6.06 g, 0.0216 mol) in CH ₂ Cl ₂ (160 ml). The reaction product was vigorously stirred and 3-carbomethoxypropionyl chloride (2.66 ml, 0.0216 mol) was added. The reaction product was vigorously stirred at 0 ° C. for 15 minutes. Water (100 ml), 1N aqueous HCl (25 ml) and E
tOAc (500 ml) was added continuously and the layers were separated. The organic layer was washed with brine, dried over Na ₂ SO ₄ ,
Filtration and concentration gave the product (6.78 g). The product was used without further purification.

B. 2 (RS), 3 (SR) -N ^2- [2
- (methoxycarbonyl) ethyl carbonyl] -N ⁶ -
Phenylmethoxycarbonyl-L-lysyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide DCC (2.85 g, 13 1.9 mmol) in THF (65 ml) precooled to 0 ° C. to produce the product (4.63 g, 12.6 mmol), Example 1
It was added to a mixture consisting of the product of 3a (5.00 g), 12.6 mmol) and HOBT (3.76 g, 27.8 mmol). The mixture was stirred at 0 ° C. for 1 hour, warmed to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was diluted with EtOAc, washed with saturated NaHCO ₃ and brine successively. The organic layer is solid K ₂ CO ₃ : Ka ₂ SO ₄
Dry on (10:90) and remove the solvent under vacuum to give the crude product. MeO on silica gel as eluent
Purification by flash chromatography using H: CHCl ₃ (1:99) gave the product as a white foam (6.22 g); TLC, R _f -0.40, silica gel, MeOH: CHCl ₃ (5: 95).

C. 3 (RS) -N ² - [2- (methoxycarbonyl) ethyl carbonyl] -N ⁶ - [(phenylmethoxy) carbonyl] -L- lysyl -L- valyl -N
-[3- (4-methyl-1,1,1-trifluoro-2
-Oxopentyl)]-L-prolinamide dry CH ₂
DMSO (15.9 g, 100 in Cl ₂ (50 ml)
(mmol) solution cooled to -43 ° C, dry CH ₂ C
Oxalyl chloride (8.8 ml, l ₂ (150 ml),
200 mmol) was added under nitrogen to a stirred solution. CH ₂
The product of Example 13b (6.22) in Cl ₂ (60 ml).
g, 8.37 mmol) was added in a similar manner.
The reaction mixture was stirred at −20 ° C. for 1 hour and TEA (70 m
1, 400 mmol) was added dropwise. Allow the mixture to warm slowly to room temperature and stir for another 1 h, then CH ₂
Dilute with Cl ₂ and wash with 5% aqueous NaOCl to give solid K ₂
Dry over CO ₃ : Na ₂ SO ₄ (10:90), filter and remove the solvent under vacuum to give the crude product. Purification by flash chromatography on silica gel with MeOH: CHCl ₃ (1:99) as eluent gave the product (4.5 g) as a pale yellow foam; TL
C, R _f = 0.51, silica gel, MeOH: CHCl ₃
(1: 9); HPLC, t R = 6.99 and 12.0
1, flow rate = 1 ml / min, Tuolvacs ODS analytical column, H ₂ O: CH ₃ CN: TEF (50: 50: 0.
1).

Example 14 3 (RS) -N ² -[(2-carboxyethyl) carbonyl] -N ⁶ -[(phenylmethoxy) carbonyl]-
L- lysyl -L- valyl -N- [3- (4-methylation -
1,1,1-trifluoro-2-oxopentyl)]-
L-prolinamide MeOH (60 ml) and 1NN
A solution of the product of Example 13c (2.0 g, 2.7 mmol) in aOH (5.4 ml, 5.4 mmol) was stirred at room temperature for 12 h, then 1N aqueous HCl (6.0 ml, 6.0 mL).
pH 7 with (mMole). MeOH was removed under vacuum. The resulting residue was dissolved in EtOAc, washed with brine, dried over MgSO _4, filtered to give the the solvent was removed in vacuo the crude product. On silica gel (pH 5.5, B
Aker.RTM., purification by flash chromatography with chloroform gave the product (1.7 g) as a white foam; HPLC, t _R = 4.0.
6 and 5.56, flow rate = 1 ml / min, Tsuorubakkusu ODS analytical _{column, H 2 O: CH 3 CN} : TFA (5
0: 50: 0.1).

Calculated: C ₃₄ H ₄₈ N ₅ O ₉ F ₃ 1.75H ₂ O: C, 53.78; H, 6.83; N, 9.22 Measured:
C, 53.46; H, 6.39; N, 9.03 Example 15 3S (or R) -N ^2, N ⁶ - di [(phenylmethoxy) carbonyl] -L- lysyl -L- valyl -N -[3
-(4-methyl-1,1,1-trifluoro-2 -oxy)
Sopentyl)]-L-prolinamide a. 2 (RS),
^{3 (SR) -N 2, N} 6 - di [(phenylmethoxy) carbonyl] -L- lysyl -L- valyl -N- [3- (4-
Methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide DCC (0.93 g, 4.
49 mmol) with N ² , N ⁶ -benzyloxycarbonyl-
L-lysine (1.69 g, 4.08 mmol), the product prepared using the method of Example 3d (1.50 g, 4.08 mmol).
Mol), 1-hydroxybenzotriazole (1.10)
g, 8.16 mmol) and anhydrous THF (75 ml) was added at 0 ° C. under nitrogen. Reaction mixture at 0 ° C
Stirred for 1 h, then allowed to warm to room temperature and stir overnight. The reaction mixture was filtered. The filtrate was evaporated to dryness. The residue was dissolved in CHCl ₃ and the solution was treated with 1N aq.
It was washed with Cl and brine and dried over Na ₂ SO ₄ .
Na ₂ SO ₄ was filtered and the filtrate was concentrated under vacuum to give a crude product (3.94 g) which was purified by silica gel onto CHC.
_{l 3: MeOH (95: 5} ) flash chromatography using - was purified by. 2.48 _{g of} product were obtained; TLC, R _f = 0.36-0.56, CHCl ₃ : M
OH (95: 5), silica gel; HPLC, Tuolvacs ODS analytical column, flow rate = 1.5 ml / min,
_{CH 3 CN: H 2 O (} 50:50); t R = 18.33,
14.99.

Calculated value: C ₃₃ H ₄₁ F ₃ N ₄ O ₇ : C, 59.01; H, 6.24; N, 8.45 Measured value: C, 58.89; H, 6.33; N , 7.89 b. 3S (or R) -N ^2, N ⁶ - di [(phenylmethoxy) carbonyl] -L- lysyl -L- valyl -N-
[3- (4-methyl-1,1,1-trifluoro-2-
Oxopento-yl)]-L-prolinamide DMSO (2.8 g, 36.13 mmol) and dry C
A solution of H ₂ Cl ₂ (40 ml) was added to a stirred solution of oxalyl chloride and dry CH ₂ Cl ₂ (40 ml) at −60 ° C. under nitrogen. Then the product of Example 15a (2.30 g,
A solution of the product of 3.01 mmol) and dry CH ₂ Cl ₂ (40 ml) was added to the reaction mixture at −50 ° C. The resulting reaction mixture was stirred at -60 ° C for 1 hour. Triethylamine (7.290 g, 72.26 mmol) was added,
The reaction product was allowed to warm to room temperature. The mixture was washed twice with 1N aq. HCl, then brine, and Na ₂ SO ₄
Dried on. Na ₂ SO ₄ was filtered and the filtrate was concentrated under vacuum to give a crude product (2.67 g). The product was purified by flash chromatography on silica gel with CHCl ₃ : MeOH (97: 3) to give product 64.
mg obtained; TLC, R _f = 0.6, CHCl ₃ : MeO
H (95: 5); HPLC , Tsuorubakkusu ODS analytical _{column, CH 3 CN: H 2 O} (60:40), flow rate = 1.
5 ml / min, t _R = 5.29.

Calculated value: C ₃₈ H ₅₀ F ₃ N ₅ O ₈ .H ₂ O: C, 58.53; H, 6.72; N, 8.98 Measured value: C, 58.95; H, 6 .59; N, 8.74 Example 16 3 (RS) -1- (12-methoxy-12-oxododecyloxy) carbonyl-N- [3- (1,1,1-trifluoro-4-methyl-2. -Oxopentyl)]-L
- prolinamide (Formula ^{Ia, R 7 = CH (CH} 3) C
H ₃ , R ³ = CH ₃ OCO (CH ₂ ) ₁₁ , A = OCO, n =
1) a. Methyl 12-hydroxy dodecanoic acid salts of 1-hydroxy-dodecane salt (4.0 g, 18.5 m mol), MeOH (450ml), concentrated H ₂ SO ₄ (2.5
ml), and a mixture of 3A molecular sieves (3 ml) were stirred at reflux for 16 hours. The mixture is saturated with NaHC
Neutralized with aqueous O ₃ solution, concentrated in vacuo and partitioned between Et ₂ O and water. Wash the ether solution (water, saturated NaHC
O ₃ aqueous solution, brine), dried (Na ₂ SO _4), filtered, and concentrated under vacuum, the product as a white solid (3.94 g) was obtained; NMR (DMSO-d ₆₎ δ8
3.65 (3H, s); 1.7-1.0 (22H,
m).

B. 11-Methoxycarbonyl undecyl 4-nitrophenyl carbonate Using the method of Example 6a, converting the product of Example 16a into the title compound, flash chromatography- (EtOAc:
The title compound was purified by hexane (1: 9) to give 5
Obtained in 9% yield; TLC, _Rf = 0.20, EtOA.
c: hexane (1: 9).

C. 2 (RS), 3 (SR) -1- (12
- methoxy-12-oxo-dodecyloxy) carbonyl -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VIIa, R ¹ = CH ( CH ₃ ) CH ₃ , R ³ = CH ₃
OCO (CH ₂ ) ₁₁ , A = OCO, n = 1) Using the method of Example 6b, allowing the product of Example 16b to react with the material prepared using the method of Example 2b, by flash chromatography. After purification (acetone: hexane (3: 7)), feed the title product (45%); H
_{PLC, t R = 4.43, ColA} , CH 3 CN: H 2 O
(35:65), FR = 2.0.

D. 3 (RS) -1- (12-methoxy-
12-oxododecyloxy) carbonyl-N- [3-
(1,1,1-Trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (Formula Ia, R ¹ = C
_{H (CH 3) CH 3,} R 3 = CH 3 OCO (CH 2) 11, A
= OCO, n = 1) To the product of Example 16c (1.1 mmol) DMSO (65
ml) and Ac ₂ O (50 mmol) were added. The resulting solution was stirred for 18 hours at room temperature, diluted with Et ₂ O.
Wash the organic solution (saturated NaHCO ₃ solution (3 times),
Water, brine), dried (Na ₂ SO ₄ ), filtered, concentrated in vacuo and by flash chromatography (Et.
₂ O: hexane (1 :) purified to give the title product (100
%) Was obtained; HPLC, t _R = 12.73, ColA,
_{CH 3 CN: H 2 O (} 60:40), FR = 2.0.

Calculated value: C ₂₂ H ₂₈ F ₃ N ₅ O ₅ 0.4H ₂ O: C, 55.91; H, 8.00; N, 5.21 Measured value: C, 56.05; H, 8.00; N, 5.19 Example 173 3 (RS) -1- (12-Hydroxy-12-oxododecyloxy) carbonyl-N- [3- (1,1,1-trifluoro-4-methyl- 2-oxopentyl)]-L
- prolinamide (Formula ^{Ia, R 1 = CH (CH} 3) C
H ₃ , R ³ = HOCO (CH ₂ ) ₁₁ , A = OCO, n =
1) Using the method of Reference Example 1, the product of Example 16d was flash chromatographed (EtOAc: hexane (1:
1)) purified and obtained in 10% yield, converted to the title compound; HPLC, t _R = 4.55, Col
_{A, CH 3 CN: H 2} O (60:40), FR = 2.0.

Calculated value: C ₂₄ H ₃₉ F ₃ N ₂ O ₆ 0.1H ₂ O: C, 56.48; H, 7.74; N, 5.49 Measured value: C, 56.48; H, 7.96; N, 5.23 Example 18 3 (RS) -1- [1-oxo-5- (phenylmethoxycarbonylamino) pentyl] -N- [3- (1,
1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (formula Ia, R ¹ = CH (C
H ₃ ) CH ₃ , R ³ = φCH ₂ OCONH (CH ₂ ) ₄ , A =
CO, n = 1) a. 5- (phenylmethoxycarbonylamino) valeric acid 5-aminovaleric acid (5.00 g, 42.68 mmol) and 2N NaOH (32.0 ml, 32.0 mmol), stirred, cooled solution (0 ° C.). ) To benzyl chloroformate (7.65 g, 6.40 ml, 44.81 m)
Mol) and 2N NaOH (32.0 ml, 32.0 m
Mol) was added simultaneously. After stirring for 0.5 h at 0 ° C., the solution was washed with Et ₂ O. Et ₂ O layer is 6N HCl
At pH 2.0, resulting in product precipitation from solution. The title compound is filtered, washed (H ₂ O),
Dry (vacuum oven) to give the pure product as a white solid (8.55 g, 80.0%). About 104-105 ° C;
About 104-105 ° C .; TLC, R _f = 0.48, MeO
_{H: CHCl 3: AcOH (3} : 97: 0.1). b.
2 (RS), 3 (SR) -1- [1-oxo-5- (phenylmethoxycarbonylamino) pentyl] -N-
[3- (1,1,1-trifluoro-2-hydroxy-
4-Methylpentyl)]-L-prolinamide (Formula VI
Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = φCH ₂ OCO
_{NH (CH 2) 4, A} = CO, n = 1) CHCl 3 in (50 ml), Example 18a product of (0.
47 g, 1.86 mmol), HOBT (0.50 g,
3.72 mmol) and DCC (0.40 g, 1.95)
To a stirred, chilled solution (0 ° C.) of the product prepared using the method of Example 2b (0.50 g, 1.
86 mmol) was added. After stirring the reaction mixture overnight at room temperature, it was filtered, concentrated and partially EtOA.
A syrup dissolved in c was obtained. Insoluble substance is EtOA
c solution, then washed (saturated aqueous NaHCO ₃ solution, 5% aqueous citric acid solution and brine), dried (N 2
a ₂ SO _4), and concentrated, the mixture is then flash chromatography - purified by (MeOH: CHC
l ₃ (4:96)) The product was obtained as a white foam (0.78 g, 84%); TLC, R _f = 0.4, Me.
OM: CHCl ₃ (4:94).

C. 3 (RS) -1- [1-oxo-5-
(Phenylmethoxycarbonylamino) -pentyl]-
N- [3- (1,1,1-trifluoro-4-methyl-
2-oxopentyl)]-L-prolinamide (formula I
a, R _f = CH (CH ₃ ) CH ₃ , R ³ = φCH ₂ OCON
H (CH ₂ ) ₄ , A = CO, n = 1 The product of Example 18b (1 mmol) was added to DMSO (85 mmol) and Ac ₂ O (64 mmol). The resulting solution was stirred at room temperature for 18 hours, poured into ice water (50 ml) and stirred for 1-4 hours. The crude product was extracted into EtOAc, the EtOAc solution was washed (saturated aqueous NaHCO ₃ solution, brine), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo, after which the product was purified by flash chromatography. Purified (CHCl ₃ : MeOH (97:
3)) product (58%) was obtained; HPLC, t _R = 6.
56 and _{7.79, ColA, H 2 O:} CH 3 CN (6
0:40), FR = 2.0.

Calculated: C ₂₄ H ₃₂ F ₃ N ₃ O ₅ .1.5H ₂ O: C, 54.74; H, 6.69; N, 7.98 Measured value: C, 54.87; H , 6.20; N, 8.02 Example 19 3 (RS) -1- (1-oxo-4-phenoxybutyl) -N- [3- (1,1,1-trifluoro-4-methyl-2- Oxopentyl)]-L-prolinamide (formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = φO (CH
₂ ) ₃ , A = CO, n = 1) a. 2 (RS), 3 (SR) -1- (1-oxo-4-
Phenoxybutyl) -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L
- prolinamide (Formula ^{VIIa, R 1 = CH (CH} 3) C
H ₃ , R ³ = φO (CH ₂ ) ₃ , A = CO, n = 1) A molar equivalent of CDI was added once to a 0.25M solution of 4-phenoxybutanoic acid in THF. After stirring the reaction mixture at room temperature for 1 hour, the molar equivalents of product prepared using the method of Example 2b were added in one portion. After stirring the reaction product overnight, excess saturated aqueous NaHCO ₃ solution was added; the mixture was extracted with EtOAc. The EtOAc extract was washed (HCl, brine), dried (MgSO _4), filtered, and concentrated under vacuum to give the title product (88%): TLC, R f = 0.53 and 0.61, MeO
_{H: CH 2 Cl 2 (1} : 9).

B. 3 (RS) -1- (1-oxo-4-
Fuenokishibuchiru) -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula ^{Ia, R 1 = CH (CH} 3) CH 3, R 3
= ΦO (CH ₂ ) ₃ , A = CO, n = 1) The product of Example 19a was converted to the title compound in 39% yield after recrystallization from water by the method of Example 18c; TLC;
R _f = 0.68 and 0.64, CH ₂ Cl ₂ : MeOH
(9: 1).

Calculated: C ₂₁ H ₂₇ F ₃ N ₂ O ₄ .1.25H ₂ O: C, 55.93; H, 6.59; N, 6.21 Measured: C, 55.88; H , 6.67; N, 6.15 Example 20 3 (RS) -1- [2- (4-morpholinyl) ethoxycarbonyl] -N- [3-1,1,1-trifluoro-4.
- methyl-2-oxopentyl)] - L-prolinamide (Formula ^{Ia, R 1 = CH (CH} 3) CH 3, R 3 = 4- morpholinyl _{- (C H 2) 2,} A = OCO, n = 1 ) A. 2-
Example 6 with the exception of (4-morpholinyl) ethyl 4-nitrophenyl carbonate hydrochloride pyridine (and acid wash).
2- (4-morpholinyl) ethanol was treated with 4-nitrophenyl chloroformate using the method of a.
The crude product was filtered, washed with Et ₂ O and dried under vacuum. The product obtained (91%) was used in the next reaction without further identification.

B. 2 (RS), 3 (SR) -1- [2-
(4-morpholinyl) ethoxycarbonyl] -N- [3
-1,1,1-Trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide (Formula Ia, R ¹
_{= CH (CH 3) CH 3} , R 3 = 4- morpholinyl - (C
H ₂ ) ₂ , A = OCO, n = 1) Using the method of Example 6b,
The product of Example 20a reacts with the product prepared using the method of Example 2b to give the title product (68%) after purification by flash chromatography (MeOH: CH ₂ Cl ₂ (1:99)). Allowed; TLC, R _f = 0.
34, MeOH: CHCl ₃ (5:95), FR = 2.
0.

C. 3 (SR) -1- [2- (4-morpho
(Rinyl) ethoxycarbonyl] -N- [3-1,1,1
-Trifluoro-4-methyl-2-oxopentyl)]
-L-prolinamide (Formula Ia, R¹= CH (CH₃) C
l₃, R³= 4-morpholinyl- (CH₂)₂, A = OC
O, n = 1) DM in the product of Example 20b (1.1 mmol)
SO (65 mmol) and Ac₂Add O (50 mmol)
Added The resulting solution was stirred at room temperature for 18 hours, CH₂C
l₂Diluted. Wash the organic solution (saturated NaHCO 3
₃Wash (3 times), water, and brine), dry (N.
a₂SO_Four), Filter, concentrate under vacuum, then flush.
Chromatography (MeOH: CHCl₃(2: 9
8)) to give the title product (37%);
HPLC, t_R= 8.44 and 9.88, ColA,
CH₃CN: H₂O (60:40), FR = 2.0 Calculated value: C₁₈H₂₈F₃N₃O_Five・ 1.0H₂O: C, 48.97; H, 6.85; N, 9.51 Measured value: C, 48.97; H, 6.61; N, 9.73 Example 21 3 (RS) -1- [1 -Oxo-6- [2- (2-pyri
Dil) ethoxy] carbonylamino-hexyl] -N-
[3- (1,1,1-trifluoro-4-methyl-2-
Oxopentyl)]-L-prolinamide (formula Ia, R
¹= CH (CH₃) Cl₃, R³= (2-pyridyl)-(C
H₂)₂OCONH- (CH₂)_Five, A = CO,n = 1)
a. 4-nitrophenyl 2- (2-pyridyl) eth
Le carbonate Et₂2-Pyridine ethanol in O (20 mol)
Solution (1.38 g, 11 mmol) over 1 hour
Therefore, p-nitrophenyl chloroformate (2.26
g, 11 mmol) at 0 ° C. under nitrogen.
It was The resulting mixture was stirred at 0 ° C. for 1 hour and then formed
Collected precipitates under a blanket of nitrogen and use anhydrous EtOH.
Recrystallized from the compound and expressed as a grayish white crystal.
1.53 g (58%) of the product was obtained, mp 125-127
° C.

B. 2 (RS), 3 (SR) -1- [1-
Oxo-6- [2- (2-pyridyl) ethoxy] carbonylaminohexyl] -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-
L- prolinamide (Formula ^{VIIa, R 1 = CH (CH} 3)
CH ^_3, R ₃ = (2- pyridyl) (CH _{2) 2} OCONH
_{(CH 2) 5, A-} CO, n = 1) Example 37b Amino product (0.75 g, 1.8 m mol), Example 2a product (0.675 g, 1.8 m mol), TEA (0 .52 m
l, 3.6 m mol), and the solution stirred at room temperature for 2 days in CH ₃ CN (25 ml) and water (25 ml), then to obtain a solvent was removed under nitrogen the crude product was purified by flash chromatography which - by (CH ₃ OH: CHCl ₃ (2.
5: 97.5)) purified to give the product (1.13 mmol, 60%) as a blue-yellow solid; TLC, R _f =.
_{0.5, CH 3 OH: CHCl 3} (5:95).

C. 3 (RS) -1- [1-oxo-6-
[2- (2-pyridyl) ethoxy] carbonyl-aminohexyl] -N- [3-trifluoro-4-methyl-2
-Oxo-pentyl)]-L-prolinamide (formula I
a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = (2-pyridyl)
_{- (CH 2) 2 OCOH (} CH 2) 5, A = CO, n = 1) Using the method of Example 18c, instead of the representation carbonyl) The product of Example 21c, flash chromatography - after purification by (MeOH: CHCl ₂ (3:97)), the title product was obtained in 10% yield; HPLC, t _R = 1.84.
ColA, H ₂ O: CH ₃ CN (60:40), FR =
2.0.

Calculated value: C ₂₅ H ₃₅ F ₃ N ₄ O ₅ .0.5H
₂ O: C, 55.85; H, 6.75; N, 10.40 Calculated: C, 56.08; H, 6.82; N, 10.4
3 Example 22 3 (RS) -1- [2-phenylmethoxy-1- (phenylmethoxymethyl) ethoxycarbonyl] -N- [3
-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (formula Ia, R ¹ =
_{CH (CH 3) C H 3} , R 3 = (φCH 2 OCH 2) CH,
A = OCO, n = 1) a. 4-Nitrophenyl 2-phenylmethoxy-1-
(Phenylmethoxymethyl) ethyl carbonate temperature TEA (0.74 g, 7.34 mmol) was added to a stirred solution of p-nitrophenyl chloroformate (1.48 g, 7.34 mmol) and Et ₂ O (30 ml). 0 ℃ ~ 5
It was added dropwise at ° C. To the above reaction mixture was added 1,3-dibenzylglycerol (2.0 g, 7.34 mmol) and E.
A solution of t ₂ O (20 ml) was added at 0 ° C. to 5 ° C. and the resulting mixture was stirred at 0 ° C. to 5 ° C. for 2 hours, then warmed to room temperature and allowed to stir overnight. The reaction mixture was filtered and concentrated in vacuo to give a yellow oil. 3.6g may remain, by flash chromatography - _{(hexanes: Et 2 O (8: 2} )) to give the title compound 2.19 g (68%) as a clear oil; TLC,
_Rf = 0.33, hexane: ether (7: 3).

B. 2 (RS), 3 (SR) -1- [2-
Phenylmethoxy-1- (phenylmethoxy-methyl)
Ethoxycarbonyl] -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-
L- prolinamide (Formula ^{VIIa, R 1 = CH (CH} 3)
CH ₃ , R ³ = (φCH ₂ OCH ₂ ) CK, A = OCO, n
= 1) using the method of Example 6b, allowing the product of Example 22a to react with the product prepared using the method of Example 2b,
Flash chromatography - (CHCl _3: EtOA
After purification by c (95: 5)), the title compound (62%)
The resulting; HPLC, t _R = 5.81 and 6.29,
ColA, H ₂ O: CH ₃ CN (40:60), FR =
2.0.

C. 3 (RS) -1- [2-phenylmethoxy-1- (phenylmethoxymethyl) -ethoxycarbonyl] -N- [3- (1,1,1-trifluoro-4]
-Methyl-2-oxopentyl)]-L-prolinamide (formula Ia, R ¹ = CH (C ₃ H) CH ₃ , R ³ = (φCH
₂ OCH ₂ ) ₂ CH, A = OCO, n = 1) The product of Example 22b is oxidized using the method of Example 18c,
Flash chromatography (CHCl ₃ : EtOAc
(98: 2)) after purification by to give the title compound (13%); HPLC, t R = 5.62, ColA, H 2 O: C
_{H 3 CN (40:60), FR} = 2.0.

Calculated: C ₂₉ H ₃₅ F ₃ N ₂ O ₆ 0.25H ₂ O: C, 61.20; H, 6.28; N, 4.92 Measured value: C, 61.28; H , 6.34; N, 5.15 d. 3 (RS) -1- [2-phenylmethoxy-1-
(Phenylmethoxymethyl) -ethoxycarbonyl]-
N- [3- (1,1,1-trifluoro-4-methyl-
2-oxopentyl)]-L-prolinamide (formula I
a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ (φCH ₂ OCH ₂ )
₂ CH, A = OCO, n = 1).

Using the method of Example 18c, the product of Example 22b was oxidized and flash chromatographed (CHCl.
₃ to EtOAc: after purification by (98 2)) to give the title product (13%); HPLC, t R = 5.62, Co
1A, H ₂ O vs. CH ₃ CN (40:60), FR = 2.
0.

As analytical C ₂₉ H ₃₅ F ₃ N ₂ O ₆ 0.25H ₂ O: Calculated: C61.20; H6.28; N4.92 Found: C61.28; H6.34; N5.15. Example 23 3 (RS) -1- [1-oxo-4- (1-oxo-2
-Phenoxyethylamino) butyl] -N- [3-
(1,1,1-Trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (Formula Ia, R ¹ = C
H (CH ₃ ) CH ₃ , R ³ = φOCH ₂ CONH (C
H ₂ ) ₃ , A = CO, n = 1) a. Ethyl 4- (1-oxo-2-phenoxyethylamino) butanoate To a stirred mixture of ethyl 4-aminobutanoate hydrochloride (3.4 g) and phenoxyacetyl chloride (2.76 ml) in 50 ml Et ₂ O and 50 ml water. , Na
HCO ₃ (4.2 g) was added at once. After 2 hours, the layers were separated and the organic layer washed (1N HCl, brine), dried (MgSO _4), and filtered. After evaporation of the solvent under vacuum, 3.1 g (53%) of the title compound was obtained as an oil.

B. Example 23 in 1-NaOH 4- (1-oxo-2-phenoxyethylamino) butyric acid (15 ml)
The product of a (3.1 g) was stirred at room temperature for 6 hours. The resulting solution was acidified with 2N HCl. The precipitated solid was collected, washed with water and dried under high vacuum.
2.5 g (95%) of the title compound was obtained as a white solid (mp 91-91).
94 ° C.).

C. 2 (RS), 3 (SR) -1- [1-
Oxo-4- (1-oxo-2-phenoxyethylamino) butyl] -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide (formula VIIa, R ¹ = CH (CH ₃ ) ₃ , R ³ =
φOCH ₂ CONH (CH ₂ ) ₃ , A = CO, n = 1), using the method of Example 19a, the product of Example 123b
Was reacted with the product prepared using the method described above to give the title product (92%) after acid and base wash workup; TL
C, Rf = 0.43 & 0.48, MeOH vs. CH ₂ Cl ₂
(1: 9).

D. 3 (RS) -1- [1-oxo-4-
(1-Oxo-2-phenoxyethylamino) -butyl] -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (Formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = φOCH ₂
CONH (CH ₂ ) ₃ , A = CO, n = 1).

Using the method of Reference Example 6c, the product of Example 23d was oxidized and subjected to flash chromatography (MeO 2).
After purification with H vs. CH ₂ Cl ₂ (3:97)) the title product (75%) was obtained: HPLC, t _R = 4.62 & 6.
02, ColA, CH ₃ CN vs. H ₂ O (65:35), F
R = 2.0.

Analysis As C ₂₃ H ₃₀ F ₃ N ₃ O ₅ : Calculated: C56.26; H6.28; N8.56 Found: C56.28; H6.40; N8.30 Example 243 (RS) -1- (4-Methoxy-1,4-dioxobutyl) -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (Formula Ia, R _{^{1 = CH (CH 3) CH}} 3, R 3 = CH 3 OC
O (CH ₂ ) ₂ , A = CO, n = 1) a. 2 (RS), 3 (SR) -1- (4-methoxy-
1,4-dioxobutyl) -N- [3- (1,1,1-
Trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide (Formula VIIa, R ¹ = CH
(CH ₃ ) CH ₃ , R ³ = CH ₃ OCO (CH ₂ ) ₂ , A = C
O, n = 1).

CH ₂ Cl ₂ (50 m
1) and 1N NaOH (6 ml) to a stirred mixture of the product (1.34 g) prepared using the method of Example 2b,
3-carbomethoxypropionyl chloride (0.75
g) was added dropwise. After 1 h the layers were separated and the organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated to give 1.1 g (58%) of the title compound as a white powder; TLC, R
f = 0.57, MeOH pair _{CH 2 Cl 2 (1: 9} ).

B. 3 (RS) -1- (4-methoxy-
1,4-dioxobutyl) -N- [3- (1,1,1-
Trifluoro-4-methyl-2-oxopentyl)]-
L-prolinamide (Formula Ia, R ¹ = CH (CH ₃ ) CH
₃ , R ³ = CH ₃ OCO (CH ₂ ) ₂ , A = CO, n =
1).

The product of Example 24a was oxidized using the method of Reference Example 6c to give a flash chromatograph (MeOH).
After purification with CH ₂ Cl ₂ (2:98)), the title product (71%) was obtained; TLC, Rf = 0.58, MeOH.
Vs. _{OH 2 Cl 2 (1: 9} ).

Analytical As C ₁₆ H ₂₃ F ₃ N ₂ O ₅ .0.75H ₂ O: Calculated: C48.79; H6.27; N7.11 Found: C49.04; H6.12; N6.83. Example 25 3 (RS) -1- [3- (1,1-dimethylethoxycarbonyl) amino-1-oxopropyl] -N- [3-
(1,1,1-Trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (Formula Ia, R ¹ = C
H (CH ₃ ) CH ₃ , R ³ = (CH3) 3CONH
(CH2) 2, A = CO, n = 1) a. 2 (RS), 3 (SR) -L- [3- (1,1-dimethylethoxycarbonyl) amino-1-oxopentyl)]-
L- prolinamide (Formula ^{VIIa, R 1 = CH (CH} 3) C
H ₃ , R ³ = (CH ₃ ) ₃ COCONH (CH ₂ ) ₂ , A = C
O, n = 1).

Using the method of Example 19a, 3- (BOC amino) propionic acid was reacted with the product prepared using the method of Example 2b to give the title product (80%); TL
C, Rf = 0.35, MeOH vs. CH ₂ Cl ₂ (1:
9).

B. 3 (RS) -1- [3- (1,1,1
-Dimethylethoxycarbonyl) amino-1-oxopropyl] -N- [3- (1,1,1-trifluoro-4)
- methyl-2-oxopentyl)] - L-prolinamide (Formula ^{Ia, R 1 = CH (CH} 3) CH 3, R 3 = (C
_{H 3) 3 COCONH (CH 2} ) 2, A = CO, n = 1).

Using the method of Reference Example 6c, the product of Example 25a was oxidized and subjected to flash chromatography (MeO 2).
The title product (61%) was obtained after purification by H vs. CH ₂ Cl ₂ (2:98); TLC, Rf = 0.46, MeOH.
Vs _{CH 2 Cl 2 (1: 9} ).

Analytical As C ₁₉ H ₃₀ F ₃ N ₃ O ₅ .0.75H ₂ O: Calculated: C50.83; H6.62; N9.39 Found: C51.18; H7.00; N9.28. Example 26 3 (RS) -1- (3-benzoylamino-1-oxopropyl) -N- [3- (1,1,1-trifluoro-
4-Methyl-2-oxopentyl)]-L-prolinamide (formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = φCO
_{NH (CH 2) 2, A} = CO, n = 1) a. 2 (RS), 3 (SR) -1- (3-benzoylamino-1-oxopropyl) -N- [3- (1,1,1
-Trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide (Formula VIIa, R ¹ = CH
(CH ₃ ) ₃ , R ³ = φCONH (CH ₂ ) ₂ , A = CO, n
= 1).

Using the method of Example 19a, 3- (benzoylamino) propionic acid was reacted with the product prepared using the method of Example 2b to give the title product (83%); T
LC, Rf = 0.39 & 0.42, MeOH vs. CH ₂ C
₁₂ (1: 9).

B. 3 (RS) -1- (3-benzoylamino-1-oxopropyl) -N- [3- (1,1,1
-Trifluoro-4-methyl-2-oxopentyl)]
-L- prolinamide (Formula ^{Ia, R 1 = CH (CH} 3) C
H ₃ , R ³ = φCONH (CH ₂ A = CO, n = 1).

Using the method of Reference Example 6c, the product of Example 26a was oxidized and subjected to flash chromatography (MeO 2).
H to CH ₂ Cl ₂ (2:98))) to give the title product (48%); TLC, Rf = 0.54, MeO.
H vs _{CH 2 Cl 2 (1: 9} ).

Analysis As C ₂₁ H ₂₆ F ₃ N ₃ O ₄ : Calculated: C57.14; H5.94; N9.52 Found: C57.12; H6.59; N9.45 Example 273 (RS) -1- [3- (1-oxo-2,2-diphenylethyl) amino] -1-oxobutyl-N- (3-
(1,1,1-Trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (Formula Ia, R ¹ = C
H (CH ₃ ) CH ₃ , R ³ = φ ₂ CHCONH (CH ₂ ) ₃ ,
A = CO, n = 1). a. Ethyl 3- (1-oxo-
2,2-diphenylethyl) aminobutanoate.

To a stirred solution of ethyl 4-aminobutyrate hydrochloride (2.51 g) and diphenylacetyl chloride (3.46 g) in 50 ml of CH ₂ Cl ₂ was added 50 ml of water, then NaHCO ₃ (3.4 g). Was added at once.
After 2 hours the layers were separated and the organic phase was dried (Na ₂ SO ₄ ).
, Filtered and evaporated. 3.5 g of the title compound (72
%) Was obtained as a white solid; TLC, R _f = 0.
71, MeOH pair CH ₂ Cl ₂ (5:95).

B. 3- (1-Oxo-2,2-diphenylethyl) aminobutyric acid The product of Example 27a (3.5 ml) in 1N NaOH (30 ml) and EtOH (10 ml).
The mixture of g) was stirred for 10 hours. Then the solution is Et
Extracted with ₂ O. The aqueous phase was acidified with 2N HCl and the solid that precipitated was collected, washed with water and dried under high vacuum. 2.9 g (93%) of the title compound was obtained as a white powder.

C. 2 (RS), 3 (SR) -1- [3-
(1-oxo-2,2-diphenylethyl) amino-1
- oxobutyl-N-[3- (1,1,1-trifluoro-2-hydroxy-4-Mechirupechiru)] - L-prolinamide (Formula ^{VIIa, R 1 = CH (CH} 3) CH 3, R 3
= Φ ₂ CHCONH (CH ₂ ) ₃ , A = CO, n = 1).

Using the method of Example 19a, the product of Example 22b was reacted with the product prepared using the method of Example 2b to give the title product (81%); TLC, R _f = 0. 1
3, MeOH pair CH ₂ Cl ₂ (5:96).

D. 3 (RS) -1- [3- (1-oxo-2,2-diphenylethyl) amino-1-oxobutyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxo Pentyl)]-L-prolinamide (formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = φ ₂ CHCON
H (CH ₂ ) ₃ , A = CO, n = 1).

Using the method of Reference Example 6c, the product of Example 27c was oxidized and subjected to flash chromatography (MeO 2).
The title product (27%) was obtained after purification by H vs CH ₂ Cl ₂ (2:98); TLC, R _f = 0.24, MeOH vs CH ₂ Cl ₂ (5:95).

As analysis C ₂₉ H ₃₄ F ₃ N ₃ O ₄ .1.0H ₂ O: Calculated value: C, 61.31; H, 6.48; N, 7.39 Found value: C, 61.58 H, 6.77; N, 7.43 Example 28 3 (RS) -1- [2- (2-methoxyethoxy) ethoxycarbonyl] -N- [3- (1,1,1-trifluoro-4] - methyl-2-oxopentyl)] - L-prolinamide (formula ^{Ia, R 1 = CH (CH} 3) CH 3, R 3 = C
H ₃ O (CH ₂ ) ₂ O (CH ₂ ) ₂ , A = OCO, n = 1)
a. 2 (RS), 3 (SR) -1- [2- (2-methoxyethoxy) ethoxycarbonyl] -N- [3- (1,
1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide (Formula VIIa, R ¹ =
_{CH (CH 3) CH 3,} R 3 = CH 3 O (CH 2) 2 O (CH
₂ ) ₂ , A = OCO, n = 1) Using the method of Example 6b, allowing the product of Reference Example 2a to react with the product prepared using the method of Example 2b, on silica gel, acetone: Dry column flash chromatography using a gradient eluent with hexane (10:90) to (50:50).
The title compound (75%) was supplied after purification by; TL
C, R _f = 0.30 and 0.35, acetone: hexane (40:60) b. 3 (RS) -1- [2- (2-methoxyethoxy) ethoxycarbonyl] -N- [3-
(1,1,1-Trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (Formula Ia, R ¹ = C
_{H (CH 3) CH 3,} R 3 = CH 3 O (CH 2) 2 O (C
_{H 2) 2, A = OCO} , using the method of n = 1) Reference Example 6c, to oxidize the product of Example 28a, flash chromatography - in accordance _{(acetone: CHCl 3 (1: 3)} )
After purification, supply the title compound (42%); HPLC,
t _R = 5.69, ColA, H ₂ O: CH ₃ CN (75:
25), FR = 2.0.

Calculated: C ₁₇ H ₂₇ F ₃ N ₂ O ₆ : C, 49.39; H, 6.83; N, 6.78 Found: C, 49.27; H, 6.80; N , 6.48 Example 29 3 (RS) -1- [1,4-dioxo-4- (phenylmethylamino) butyl] -N- [3- (1,1,1-trifluoro-4-methyl- 2-oxopentyl)]-L-
Prolinamide (formula Ia, R ¹ = CH (CH ₃ CH ₃ ),
R ³ = φCH ₂ NH CO (CH ₂ ) ₂ , A = CO, n = 1) a. Benzylamine 4-oxo-4- (phenylmethylamino) butanoate (10.7 g) and succinic anhydride (10 g) were stirred in THF (11) for 2 days. The solid was filtered and dissolved in 1N NaOH (110 ml). The aqueous phase was washed with Et ₂ O and then acidified with concentrated HCl while cooling in an ice water bath. The solid was collected, washed with water and dried under high vacuum. 10.9 g (53%) of the title compound was obtained as a white powder. Melting point 137.5
138 ° C.

B. 2 (RS), 3 (SR) -1- [1,
4-dioxo-4- (phenylmethylamino) butyl]
-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methyl - pentyl)] - L-prolinamide (Formula ^{VIIa, R 1 = CH (CH} 3 CH 3), R 3 = φCH
₂ NHCO (CH ₂ ) ₂ , A = CO, n = 1) Using the method of Example 19a, the product of Example 29a was reacted with the product prepared using the method of Example 2b to give the title compound (74% ) Is supplied; TLC, R _f = 0.48, MeOH: CH ₂ C
₁₂ (1: 9).

C. 3 (RS) -1- [1,4-dioxo-4- (phenylmethylamino) butyl] -N- [3-
(1,1,1-Trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (formula Ia, R ¹ = C
H (CH ₃ CH ₃ ), R ³ = φCH ₂ NHCO (CH ₂ ) ₂ ,
A = CO, n = 1).

The product of Example 29b was oxidized using the method of Reference Example 6c to give a flash chromatograph (Me.
After purification by OH: CH ₂ Cl ₂ (2:98)) the title compound (40%) is obtained; TLC, R _f = 0.56, Me.
_{OH: CH 2 Cl 2 (1} : 9) _{Calculated: C 22 H 28 F 3 N} 3 O 4: C, 58.10; H, 6.20; N, 9.23 Found: C, 57.90 H, 6.36; N, 9.27 Example 30 3 (RS) -1- [1-oxo-3- (phenylmethoxycarbonylamino) propyl] -N- [3- (1,
1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (formula Ia, R ¹ = CH (C
H ₃ CH ₃ ), R ³ = φ CH ₂ OCONH (CH ₂ ) ₂ , A =
CO, n = 1) a. 2 (RS), 3 (SR) -1- [1
-Oxo-3- (phenylmethoxycarbonylamino)
Propyl] -N- [3- (1,1,1-trifluoro-
2-hydroxy-4-methyl - pentyl)] - L-prolinamide (Formula ^{VIIa, R 1 = CH (CH} 3 CH 3),
R ³ = φCH ₂ OCONH (CH ₂ ) ₂ , A = CO, n =
1) Reaction of CBZ-β-alanine with the product prepared using the method of Example 2b, using the method of Example 19a, to give the title compound (82%); TLC, R _f = 0.5.
_{9, MeOH: CH 2 Cl 2} (1: 9).

B. 3 (RS) -1- [1-oxo-3-
(Phenylmethoxycarbonylamino)) propyl]-
N- [3- (1,1,1-trifluoro-4-methyl-
2-oxopentyl)]-L-prolinamide (formula I
a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = φCH ₂ OCON
_{H (CH 2) 2, A} = CO, n = 1) Using the method of Example 6c, to oxidize the product of Example 30a, by flash chromatography _{- (MeOH: CH 2 Cl 2} (2:98))
Yielded the title compound (35%) after purification by TL;
C, R _f = 0.23, MeOH: CH ₂ Cl ₂ (5: 9
5).

Calculated: C ₂₂ H ₂₈ F ₃ N ₃ O ₅ .0.4H ₂ O: C, 55.20; H, 6.06; N, 8.77 Found: C, 55.28; H , 6.25; N, 8.55 Example 31 3 (RS) -1- [1-oxo-4- (phenylmethoxycarbonylamino) butyl] -N- [3- (1,1,
1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (formula Ia, R ¹ = CH (C
H ₃ ) CH ₃ , R ³ = φ CH ₂ OCONH (CH ₂ ) ₃ , A =
CO, n = 1) a. 2 (RS), 3 (SR) -1- [1
-Oxo-4- (phenylmethoxycarbonylamino)
Butyl] -N- [3- (1,1,1-trifluoro-2
- hydroxy-4-methylpentyl)] - L-prolinamide (Formula ^{VIIa, R 1 = CH (CH} 3 CH 3), R 3 =
φCH ₂ OCONH (CH ₂ ) ₃ , A = CO, n = 1) Using the method of Example 19a, CBZ-4-aminobutanoic acid was reacted with the product prepared using the method of Example 2b to give the title compound ( 72%); TLC, R _f = 0.47,
_{Et 2 O: EtOAc (1:} 1).

B. 3 (RS) -1- [1-oxo-4-
(Phenylmethoxycarbonylamino-butyl) -N-
[3- (1,1,1-trifluoro-4-methyl-2-
Oxopentyl)]-L-prolinamide (formula Ia, R
¹ = CH (CH ₃ ) CH ₃ , R ³ = φCH ₂ OCONH (C
_{H 2) 3, A = CO} , n = 1) Using the method of Example 6c, to oxidize the product of Example 31a, by preparative TLC (MeO
H: CH ₂ Cl ₂ (2.5: 97.5)) after purification,
This gives the title compound (32%); TLC, R _f = 0.6.
5 and _{0.68, MeOH: CH 2 Cl 2} (1: 9).

Example 32 3R (or S) -1- [1-oxo-4-phenoxy-2- (2-phenoxyethyl) butyl] -N- [3-
(1,1,1-Trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (formula Ia, R ¹ = C
H (CH ₃ ) CH ₃ , R ³ = [φO (CH ₂ ) ₂ CH, A =
CO, n = 1) a. Diethyl 2,2-di (2-phenoxyethyl) malonate To a stirred solution of sodium (2.3 g) in absolute EtOH (50 ml) was added diethyl malonate (15.2 ml) followed by 2-phenoxyethyl chloride. (15.7 g) was added. The reaction mixture is then 1
Refluxed for 2 hours. EtOH was evaporated to dryness and the mixture was diluted with water (40 ml). The aqueous layer was extracted with Et ₂ O. The combined Et ₂ O extracts were washed (brine), dried (MgSO ₄ ), filtered and evaporated. Valve to
Bulb to bulb distil
diester 12.2 as a clear liquid.
boiling point 155-175 ° (106
Pa, 0.8 torr); TLC, R _f = 0.34, CH ₂ C
l ₂ .

B. 4-Phenoxy-2- (2-phenoxyethyl) butanoic acid A mixture of the product of Example 32a (10.0 g) and potassium hydroxide (17.7 g) in water (22 ml) was refluxed for 4 hours. The reaction mixture was cooled and acidified with concentrated HCl.
The precipitated solid was collected, washed with water and air dried. The solid obtained (8.44 g) was heated at 170 ° C. for 2 hours and then cooled. Recrystallization from cyclohexane gave 4.1 g (93) of the title compound as fine white needles.
%) Was obtained; melting point 85-86 ° C.

Calcd: C ₁₈ H ₂₀ O ₄ : C, 71.98; H, 6.71 Found: C, 71.92; H, 6.71 c. 4-Phenoxy-2- (2-phenoxyethyl) butanoyl chloride A mixture of the product of Example 32b (1.5 g) and thionyl chloride (0.73 ml) was heated in a steam bath for 1 hour. The reaction mixture was then removed. The title compound, the acid chloride, was obtained quantitatively as a clear oil,
Used directly.

D. 2 (RS), 3 (SR) -1- [1-
Oxo-4-phenoxy-2- (2-phenoxyethyl) -butyl] -N- [3- (1,1,1-trifluoro-4-methyl-2-pentyl)]-L-prolinamide (formula VIIa, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = [φ
O (CH _{2) 2] 2} CH, A = CO, using the method of n = 1) Example 24a, is reacted with product prepared using the method of the product Example 2b Example 32c, the title compound (95%)
Yields TLC, R _f = 0.47 and 0.54, E
t ₂ O.

E. 3R (or S) -1- [1-oxo-4-phenoxy-2- (2-phenoxyethyl) butyl] -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl] )] - L-prolinamide (formula ^{Ia, R 1 = CH (CH} 3) CH 3, R 3 = [.phi.O (C
H ₂ ) ₂ ] ₂ CH ,, A = CO, n = 1) Using the method of Reference Example 6c, the product of Example 32d is oxidized to give the crude product as a mixture of diastereomers, which is Separation by flash chromatography (Et ₂ O: hexane (gradient eluent, 60:40 to 70:30)). The more rapidly eluting diastereomer was the title compound obtained in a yield of 27.7%; HPLC, t _R = 6.
94, ColA, CH ₃ CN: H ₂ O (65:35), F
R = 2.0.

Calcd: C ₂₉ H ₃₅ F ₃ N ₂ O ₅ : C, 63.49; H, 6.43; N, 5.11 Found: C, 63.39; H, 6.47; N , 5.07 Example 33 3S (or R)-[1-oxo-4-phenoxy-2-
(2-Phenoxyethyl) butyl] -N- [3- (1,
1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (formula Ia, R ¹ = CH (C
H ₃ ) CH ₃ , R ³ = [φO (CH ₂ ) ₂ ] ₂ CH, A = C
O, n = 1) The diastereomer gradually eluting from the crude diastereomeric separation described in Example 32e was a compound of the above title and was obtained in a yield of 28.3%. _{HPLC, t R = 5.04, ColA} , CH 3 C
_{H: H 2 O (65:35)} , FR = 2.0.

The results of the analysis were as follows: C ₂₉ H ₃₅ F ₃ N ₂ O ₅ : C, 63.49; H, 6.43; N, 5.11 Measured value: C, 63.50 H, 6.45; N, 5.26 Example 34 3 (RS) -1- [6-[(4-ethoxycarbonylphenyl) aminocarbonylamino] -1-oxo] hexyl-N- [3- ( 1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = 4- (CH
₃ CH ₂ OCO) φNHCONH (CH ₂ ) ₅ , A = CO,
n = 1) a. 2 (RS), 3 (SR) -1- [6-
[(4-Ethoxycarbonylphenyl) aminocarbonylamino] -1-oxo] hexyl-N- [3- (1,
1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide (Formula VIIa, R ¹ =
_{CH (CH 3) CH 3,} R 3 = 4- (CH 3 CH 2 OCO)
φNHCONH (CH ₂ ) ₅ , A = CO, n = 1) ethyl p-isocyanate benzoate (0.288 g, 1.
5 mmol) to the product of Example 37b (0.6 g, 1.5 mmol), TEA (0.15 g, 1.5 mmol) and CMF.
To a stirred solution of (20 ml) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight and then concentrated under vacuum to remove an amber residue which was washed with EtO.
Dissolved in Ac. Wash the EtOAc solution (1N HC
l), dried (MgSO ₄ ), filtered and concentrated in vacuo to give 1.15 g of an oily residue. The residue was flash chromatographed (CHCl ₃ : CH ₃ OH (9
7: 3)) yielded 0.62 g (70%) of the title compound as a white solid. TLC, R _f = 0.
28 and 0.35, CHCl ₃ : CH ₃ OH (95:
5).

B. 3 (RS) -1- [6-[(4-ethoxycarbonylphenyl) aminocarbonylamino]-
1-oxo] hexyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-
Prolinamide (Formula Ia, R ¹ = CH (CH ₃ ) CH ₃ ,
R ³ = 4- (CH ₃ CH ₂ OCO) φNHCONH (C
H ₂ ) ₅ , A = CO, n = 1).

Oxidation of the product of Example 34a using the method of Reference Example 6c gave flash chromatography (C
After purification with HCl ₃ : MeOH (97: 3)) the title product (43%) was obtained; HPLC, t _R = 12.
39 and 15.79, Col. A, H ₂ O: CH ₃ CN
(65:35), FR = 2.0.

The results of the analysis were as follows: C ₂₇ H ₃₇ F ₃ N ₄ O ₆ .1.0H ₂ O: C, 55.09; H, 6.68; N, 9.51 Measured value : C, 54.75; H, 6.63; N, 9.29 Example 35 3 (RS) -1- [6- (phenylmethoxycarbonylamino) -1-oxohexyl] -N- [3- ( 1,
1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (formula Ia, R ¹ = CH (C
H ₃ ) CH ₃ , R ³ = φCH ₂ OCONH (CH ₂ ) ₅ , A =
CO, n = 1) Oxidation of the product of Example 37a using the method of Example 18c gave flash chromatography (C
After purification with HCl ₃ : MeOH (97: 3)) the title product (31%) was obtained; HPLC, t _R = 4.0.
6, Col. A, CH ₃ CN: H ₂ O (1: 1), FR =
2.0.

The results of the analysis were as follows: C ₂₅ H ₃₄ F ₃ N ₃ O ₅ .0.5H ₂ O: C, 57.46; H, 6.75; N, 8.04 : C, 57.87; H, 6.24; N, 7.86 Example 36 3 (RS) -1- [6-[(4-hydroxycarbonylphenyl) aminocarbonylamino] -1-oxohexyl]- N- [3- (1,1,1-trifluoro-4-
Methyl-2-oxopentyl)]-L-prolinamide (formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = 4- (HO
CO) φNHCONH (CH ₂ ) ₅ , A = CO, n = 1)
The product of Example 34b was converted to the title product in 38% yield using the method of Reference Example 1; HPLC, t _R = 6.
24 and 8.0, Col. A, H ₂ O: CH ₃ CN (7
5:25), FR = 2.0.

The results of the analysis were as follows: C_{twenty five}H₃₃F₃N_FourO₆・ 2.5H₂O: C, 51.1; H, 6.50; N, 9.50 Measured value: C, 51.34; H, 5.93; N, 8.95 Example 373 (RS) -1- (6 -Phenylsulfonylamino-1
-Oxohexyl) -N- [3- (1,1,1-trif
Luoro-4-methyl-2-oxopentyl)]-L-p
Lorinamide (Formula Ia, R¹= CH (CH₃) CH₃, R³
= ΦS (O₂)NH (CH ₂ ) ₅ , A = CO, n = 1)
a. 2 (RS), 3 (SR) -1- [6- (phenylene)
Toxycarbonylamino) -1-oxohexyl] -N
-[3- (1,1,1-trifluoro-2-hydroxy
-4-Methylpentyl)]-L-prolinamide (Formula V
IIa, R¹= CH (CH₃) CH₃, R³= ΦCH₂OC
ONH (CH₂)_Five, A = CO, n = 1) DCC (6.3
5 g, 30.8 mmol) was added to N-CBZ-aminocapron
Acid (6.84 g, 25.7 mmol), prepared by the method of Example 2b
Fabricated material (6.89 g, 25.7 mmol), HOBT
(6.94 g, 51.4 mmol) and anhydrous THF (25
0 ml) was added to the stirred solution at 0 ° C. under a nitrogen atmosphere. Profit
The reaction mixture is stirred at 0 ° C. for 1 hour and then brought to room temperature.
It was warmed, stirred overnight and filtered. Concentrate the filtrate under vacuum
This gave a brown residue which was₃Dissolved in
And CHCl₃Wash the solution (20% citric acid solution),
Dried (Na₂SO_Four), Filtered and concentrated under vacuum. The rest
The residue is flash chromatographed (CHCl₃: Me
OH (97: 3)) to give a waxy solid.
This gave 8.0 g (61%) of the title compound; TLC, R_f
= 0.35, CHCl₃: MeOH (95: 5).

B. 2 (RS), 3 (SR) -1- (6-
Amino-1-oxohexyl) -N- [3- (1,1,
1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide (formula VIIa, R ¹ = CH
(CH ₃ ) CH ₃ , R ³ = H ₂ N (CH ₃ ) ₅ , A = CO, n
= 1) product of Example 37a (2.06 g, 3.99 mmol), EtOH (100 ml) and 10% Pd / C.
A mixture of (0.3 g) with a pearl shaker (Parr
shaker) on the H ^₂ 0.315Kg / cm ₂ (45p
Placed under si) for 3 hours. Mix the mixture with Celite
filtered through ite) and washed the Celite cake with EtOH. The EtOH was washed, the above filtrates were combined and concentrated in vacuo to yield 1.36 g (86%) of the title compound as a pale green waxy oil. R _f = 0.
2, CHCl ₃ : MeOH (85:15).

C. 2 (RS), 3 (SR) -1- (6-
Phenylsulfonylamino-1-oxohexyl) -N
-[3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide (Formula V
IIa, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = φS (O ₂ ).
NH (CH ₂ ) ₅ , A = CO, n = 1) benzenesulfonyl chloride (0.6 g, 1.5 mmol) was added to the product of Example 37b (0.26 g, 1.5 mmol), TEA (0. Three
g, 3.0 mmol) and anhydrous DMF (20 ml) was added at room temperature under nitrogen and the resulting mixture was stirred at room temperature overnight. DMF was removed under vacuum and a brown residue separated which was dissolved in EtOAc. The EtOAc solution was washed (1N HCl), dried (MgSO _4), and filtered. The filtrate is concentrated in vacuo and the residue is flash chromatographed (CHCl ₃ : MeOH (97: 3)).
Purified to give the title compound 0.48 as a white powder.
g (60%) were produced; TLC, R _f = 0.30 and 0.40, CHCl ₃ : MeOH (95: 5).

D. 3 (RS) -1- (6-phenylsulfonylamino-1-oxohexyl) -N- [3-
(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (formula Ia, R ¹ = CH
(CH ₃ ) CH ₃ , R ³ = φS (O ₂ ) NH (CH ₂ ) ₅ , A
= CO, n = 1) The product of Example 37c was oxidized using the method of Example 7b and flash chromatography (Et ₂
O: hexane (3: 1), then CHCl ₃ : MeOH
After purification by (97: 3) on the second column), the title product (36%) resulted. HPLC, t _R
= 8.48 and _{10.33, CH 3 CN: H 2} O (35:
65), FR = 2.0.

Example 38 3 (RS) -N ² , N ⁶ -di (phenylmethoxycarbonyl) -L-lysyl-L-valyl-N- [3- (1,1,
1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (formula Ia, R ¹ = CH (C
H ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = φC
H ₂ , R ⁴ = H, R ⁵ = φCH ₂ OCONH (CH ₂ ) ₄ , R
^{6 = H, A = OCO,} n = 1) Using the method of Example 4b, to oxidize the product of Example 15a, by flash chromatography - _{(hexane: Et 2 O (1: 1} ), then, E
The title product (56%) was obtained after purification by t ₂ O, then Et ₂ O: Et ₂ OAc (3: 1); HP
LC, t _R = 4.19 & 6.02, ColA, CH ₃ C
_{N: H 2 O (60:40)} , FR = 1.5.

Analytical value C ₃₈ H ₅₀ F ₃ N ₅ O ₈ .0.5H ₂ O: C, 59.21; H, 6.67; N, 9.03 Measured value: C, 58.93; H, 6.62; N, 8.75 Example 39 3 (RS)-[1,4-dioxo-4- (phenylsulfonylamino) butyl] -L-norleucyl-L-valyl-N- [3- (1, 1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (formula ^{Ic, R 1 = CH (CH} 3) CH 3, R 2 = CH (CH 3)
CH ₃ , R ³ = φS (O ₂ ) NHC O (CH ₂ ) ₂ , R ⁴ =
H, R ⁵ = (CH ₂ ) ₃ CH ₃ , R ⁶ = H, A = CO, n =
1) The product of Example 11 in CH ₂ Cl ₂ (20 ml) (0.
5 g, 0.87 mmol), benzenesulfonamide (0.14 g, 0.87 mmol), DMAP (0.1
1 g, 0.87 mmol) and DCC (0.18 g,
0.87 mmol) was stirred at room temperature for 4 days. The reaction mixture was filtered and concentrated under vacuum to give crude product. The product was flash chromatographed on a Baker pH 5.0 silica gel (gradient, CHC.
l _{3 to} MeOH: CHCl ₃ (2:98) to MeOH: C
Purification by HCl ₃ (5:95)) gave the title product (0.37 g); HPLC, t _R = 3.84.
& 5.03, ColA, H ₂ O: CH ₃ CN (65: 3
5), FR = 1.0.

Analytical value C ₃₂ H ₄₆ F ₃ N ₅ O ₈ S: C, 52.23; H, 6.57; N, 9.52 Measurement value: C, 51.94; H, 6.29; N , 9.37 Example 40 3 (RS)-[4- (methylsulfonylamino) -1,
4-dioxobutyl] -L-norleucyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (formula I
c, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) C
^{_{H 3, R 3 = CH 3}} S (O 2) NHCO (C H 2) 2, R 4 =
H, R ⁵ = (CH ₂ ) ₃ CH ₃ , R ⁶ = H, A = CO, n =
1) The product of Example 11 in CH ₂ Cl ₂ (20 ml) (0.
5 g, 0.87 mmol), methanesulfonamide (0.082 g, 0.87 mmol), DMAP (0.
11 g, 0.87 mmol) and DCC (0.18 g,
0.87 mmol) was stirred at room temperature for 4 days. The reaction was filtered and concentrated under vacuum to give the crude product which was partially purified by flash chromatography on a Baker pH 5.5 silica gel. The partially purified product was treated with EtOAc and aqueous 1N.
Partitioned between a mixture of HCl and brine. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated to give the title product (0.28 g); HPLC, t _R = 5.99.
& 8.95, ColA, H ₂ O: CH ₃ CN (65: 3
5), FR = 1.0 Analysis value: C ₂₇ H ₄₄ F ₃ N ₅ O ₈ S: C, 49.46; H, 6.76; N, 10.68 Measurement value: C, 49.07; H , 6.79; N, 10.4
3 Example 41 3 (RS) -N ^2- [1,4-dioxo-4-phenylsulfonylamino) butyl] -N ⁶ -phenylmethoxycarbonyl-L-lysyl-L-valyl-N- [3-
(1,1,1-Trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (Formula Ic, R ¹ = C
H (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = φ
S (O ₂ ) NHCO (CH ₂ ) ₂ , R ⁴ = H, R ⁵ = φCH ₂
OCONH ( CH ₂ ) ₄ , R ⁶ = H, A = CO, n = 1) The product of Example 14 (493 m ) in CH ₂ Cl ₂ (20 ml).
g, 0.670 mmol), benzelsulfonamide (117 mg, 0.745 mmol), DMAP (91
mg, 0.745 mmol), and DCC (153 m
g, 0.745 mmol) was stirred at room temperature for 24 hours.
The solution was diluted with EtOAc, washed (water), dried (M
gSO ₄ ), filtered and concentrated under vacuum. The crude product Baker (Baker) flash chromatography on pH5.5 silica gel _{- (CH 3 OH: CHCl 3} :
(25: 97.5)) and the title product (2
43 mg) was obtained as a white powder; TLC, R _f =
0.50, CH ₃ OH: CHCl ₃ : AcOH (5: 9
4: 1).

Analytical value: C ₄₀ H ₅₃ F ₃ N ₆ O ₁₀ S.0.75H ₂ O: C, 54.56; H, 6.24; N, 9.54 Measurement value: C, 54.52; H, 6.23; N, 9.48 example 42 3 (RS) - [1,4-dioxo-4 - [(tricyclo [3.3.1.1 ^{3 '7]} deci-1-yl) - sulfonyl Amino] butyl] -L-norleucyl-L-valyl-N
-[3- (1,1,1-trifluoro-4-methyl-2
-Oxopentyl)]-L-prolinamide (formula Ic,
R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ ,
R ³ = _{(1-adamantyl) -S (O 2) NHCO (} CH
₂ ) ₂ , R ⁴ = H, R ⁵ = (CH ₂ ) ₃ CH ₃ , R ⁶ = H, A =
CO, n = 1) a. 1-Agmantansulfinamide Product of Reference Example 7a (10.0 g, 45.7 mmol)
Slowly add concentrated ammonium hydroxide (300 ml) to
The mixture was heated at reflux for 3 hours. After distillation of the ammonium hydroxide, it captures the residue in water and extracted with Et ₂ O. E
The t ₂ O layer was washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. The crude product was purified by suction chromatography on silica gel (Et ₂ O to EtOAc) to give the product (4.2 g) as a white solid; mp 139-141 ° C. (Literature (Lit.). 14
1-142 ° C).

B. The product of Example 42a (4.0 g, 1-Agmantansulfonamide acetone (150 ml))
To the reflux solution (20.0 mmol), a saturated acetone solution of KMnO ₄ was added until a slight purple color persisted. The solution was cooled, filtered through Celite and concentrated under vacuum to give the product (3.2 g) as a solid; mp = 191-193 ° C. (Lit. 197).
˜198 ° C.); TLC, t _R = 0.80, EtOAc.

C. 3 (RS)-[1,4-dioxo-4
- [tricyclo [3.3.1.1 ^{3 '7]} deci-1-yl) sulfonylamino) butyl] -L- leucyl -L-
Baryl-N- [3- (1,1,1-trifluoro-4-
Methyl-2-oxopentyl)]-L-prolinamide (formula Ic, R ¹ ═CH (CH ₃ ) CH ₃ , R ² ═CH (CH
₃ ) CH ₃ , R ³ = (1-adamantyl) S (O ₂ ) NHC
O (CH ₂ ) ₂ , R ⁴ = H, R ⁵ = (CH ₂ ) ₃ CH ₃ , R ⁶ =
H, A = CO, n = 1) Product of Example 11 (300 mg, 0.51 mmol) in CH ₂ Cl ₂ (30 ml), DM
AP (62 mg, 0.51 mmol), WSCDI (9
9 mg, 0.51 mmol) and the product of Example 42b (1
A solution of 10 mg, 0.51 mmol) was stirred at room temperature for 16 hours. The CH ₂ Cl ₂ solution was washed (1N HCl, brine), dried (MgSO ₄ ), filtered and concentrated under vacuum. The crude product was treated with a preliminary TLC (MeOH: CHCl ₂
(1: 9)) to give the title product as a solid; TLC, _Rf = 0.56, MeOH: CH.
Cl ₂ (5:95); HPLC, t _R = 4.23 & 7.0.
5, ColA, H ₂ O: CH ₃ CN (1: 1), FR =
2.0.

Analytical value: C ₃₆ H ₅₆ F ₃ N ₅ O ₈ S.1.2H ₂ O: C, 54.22; H, 7.38; N, 7.78 Measurement value: C, 54.28; H, 7.84; N, 7.71 Reference Example 1 3 (RS)-[(2-carboxyethyl) carbonyl]-
L- valyl -N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L- flop Rorin'a
Mido 1N aqueous NaOH (0.92 ml) was added to MeOH (1
The product of Reference Example 8 (0.20 g, 0.42 in 0 ml).
(mMole) solution and the reaction mixture was stirred at room temperature overnight. 1N aqueous HCl (1 ml) was added and the reaction mixture was concentrated under vacuum to remove MeOH. The remaining aqueous solution was extracted with EtOAc, the organic layer was washed with brine,
Dry over Na ₂ SO ₄ , filter and concentrate under vacuum to give the product (0.18 g); TLC, R _f = 0.2, silica gel, MeOH: CHCl ₃ : TFA (5:94:
1); HPLC, t _R = 2.9, 5.86, applied Science Absorb Osfere (Science A)
bsorbbosphere: registered trademark) C8, 4.6 m
m × 10 cm, CH ₃ CN: H ₂ O: TFA (20: 8
0: 0.1), flow rate = 1.6 ml / min.

Reference Example 2 a. 2- (2-Methoxyethoxy) ethyl 4-nitrophenyl carbonate p-Nitrophenyl chloroformate (2.00 g, 9.92 mmol) in Et ₂ O (50 ml).
Pyridine (8 ml) was added to the above solution at 0 ° C., followed by E
t ₂ O (25 ml) solution of 2- (2-methoxy - ethoxy) ethanol (1.14g, 9.45m mol) was added over 1 hour. The resulting mixture was stirred for 12 hours at room temperature and partitioned between H ₂ O and Et ₂ O. The ether layer was washed with 5% aqueous HCl, pH 7.0 phosphate buffer, dried over MgSO ₄ , filtered and the solvent removed under vacuum. The crude product was purified by flash chromatography on silica gel eluting with EtOAc: hexane (30:70) to give the product (1.30 g) as a clear colorless oil; TLC, R _f = 0.11. ,
Silica gel, EtOAc: hexane (30:70).

Reference Example 3 a. 2 (RS), 3 (SR)-[(4-methoxyphenyl) carbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] -L-prolinamide CHCl, cooled to 0 ° C
_The product (1.50 g, 4.08 mmol) prepared using the method of Example 3d in ₃ (50 ml) and TEA (2.
CHCl ₃ (40 mmol) was added to a solution of 06 g, 20.4 mmol.
4-methoxybenzoyl chloride (0.766) in
g, 4.49 mmol) was added dropwise over 1 hour and the solution was stirred at room temperature overnight. The solvent was removed under vacuum, the residue was taken up in EtOA, 5% aqueous HCl, 20% aqueous NaO.
Washed with H, solid K ₂ CO ₃ : Na ₂ SO ₄ (10:90)
Dried above and removed the solvent under vacuum. On the crude product on silica gel, MeOH: flash chromatography while eluting with CHCl ₃ (5:95) - to afford a white product as foam a _{(1.84g); TLC, R f} = 0.33, silica gel, MeOH:
CHCl ₃ (5:95).

Calculated: C ₂₄ H ₃₄ O ₅ N ₃ F ₃ 0.3H ₂ O: C, 56.86; H, 6.88; N, 8.29 Calculated: C, 56.80; H, 6.88; N, 8.07 Reference Example 4 3 (RS)-[(2,4-dichlorophenyl) carbonyl)]-L-valyl-N- [3- (1,1,1-trifluoro-4). -Methyl-2-oxopentyl)]- L-p
Lorinamide a. 2 (RS), 3 (SR)-[(2,4
-Dichlorophenyl) carbonyl)]-L-valyl-N
-[3- (1,1,1-Trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide Using the method of Reference Example 3a, the material prepared by the process of Example 3d was converted into 2,4- Reaction with dichlorobenzoyl chloride yielded the title compound, isolated in 98% yield; T
LC, R _f = 0.54, MeOH: CHCl ₃ (5: 9
5).

B. 3 (RS)-[(2,4-dichlorophenyl) carbonyl] -L-valyl-N- [3- (1,
1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide A solution of DMSO (29.7 g, 380 mmol) in CH ₂ Cl ₂ (27 ml) was CH.
Oxalyl chloride (24.0) in ₂ Cl ₂ (350 ml).
g, 190 mmol) was added slowly to a pre-cooled (-65 ° C) solution and the resulting solution was stirred for 15 minutes, then C
A solution of the product prepared by the method of Reference Example 4a (9.4 mmol) in H ₂ Cl ₂ (250 ml) was added. After reaction-6
The mixture was stirred at 5 ° C for 1 hour, and diisopropylethylamine (4
8.9 g, 380 mmol) was added dropwise. The reaction mixture was warmed to room temperature, then washed (1N HCl, brine), dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. The residue was flash chromatographed (MeOH: CHCl ₃
(3:97)) and the title product (15
%) Occurred; HPLC, t _R = 17.93 and 18.
55, Col. A, H ₂ O: CH ₃ CN (55:45),
FR = 2.0.

The results of the analysis were as follows: C ₂₃ H ₂₈ Cl ₂ F ₃ N ₃ O ₄ .H ₂ O: C, 49.65; H, 5.43; N, 7.55 Measured value : C, 49.95; H, 5.31; N, 7.35 Reference Example 5 3 (RS)-(1,1-dimethylethoxycarbonyl)
-L-α-aminobutyryl-N- [3- (1,1,1-
Trifluoroacetic -4-methyl-2-Okisopenchi Le)] -
L-prolinamide a. 2 (RS), 3 (SR)-
(1,1-Dimethylethoxycarbonyl) -L-α-aminobutyryl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide DCC (5.90 g , 28.7 mmol),
HOBT (7.76 g, in anhydrous THF (130 ml)
57.4 mmol), BOC-α-aminobutanoic acid (5.60 g, 27.4 mmol) and 0 to a stirred solution of the material prepared in the process of Example 2b (7.00 g, 26.1 mmol). C. under nitrogen. The reaction mixture obtained is stirred at 0 ° C.
After stirring for 1 hour at room temperature, the mixture was warmed to room temperature and stirred overnight. The reaction mixture is filtered, the filtrate concentrated under vacuum and the residue Et
Redissolved in OAc. The resulting solution is saturated NaHCO 3.
₃ Washed with brine, dried (Na ₂ SO ₄ ), filtered, concentrated in vacuo and the residue flash chromatographed.
(Purification with EtOAc: CH ₂ Cl ₂ (1: 3) gave the title compound (95%); TLC, R _f = 0.2.
_{9, EtOAc: CH 2 Cl 2} (3: 7).

B. 3 (RS)-(1,1-dimethylethoxycarbonyl) -L-α-aminobutyryl-N- [3
-(1,1,1-Trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide When the product of Reference Example 5a was oxidized using the method of Reference Example 6c, flash chromatography (MeOH: CHCl ₃ (15:
After purification 98.5)), the title product (47%) occurred; HPLC, t _R = 10.21 and 14.54, C
ol. A, H ₂ O: CH ₃ CN (65:35), FR =
2.0.

The results of the analysis were as follows: C ₂₀ H ₃₂ F ₃ N ₃ O ₅ : C, 53.21; H, 7.14; N, 9.31 Measured value: C, 53.65. H, 7.21; N, 9.51 Reference Example 6 3 (RS)-[1-oxo-2- (2-thiophenyl)
Ethyl] -L-α-aminobutyryl-N- [3- (1,
1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide a. 2 (RS), 3 (S
R) -L-α-aminobutyryl-N- [3- (1,1,
1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide trifluoroacetate CH ₂
The material prepared in the process of Reference Example 5a (4.0 g, 8.84 mmol) in Cl ₂ (32 ml) and TFA (32 ml,
415 mmol) was stirred at room temperature for 22 hours, after which the solvent was removed under reduced pressure to give the crude product (5 g,> 100%) as a colorless glass which was not further purified or characterized. Was used.

B. 2 (RS), 3 (SR) -N- [3-
(1,1,1-Trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide DCC (0.3
15 g, 1.53 mmol) in anhydrous THF (20 ml)
HOBT (0.413 g, 3.06 mmol), 2-
Thiofeneacetic acid (0.222 g, 1.53 mmol), N
MM (0.154 g, 1.52 mmol) and Reference Example 6a
Material produced by (0.650 g, 1.39 mmol)
Was added to the stirred solution at 0 ° C. under nitrogen. The resulting reaction mixture was stirred at 0 ° C. for 1 hour, then warmed to room temperature and stirred overnight. The reaction mixture is filtered, the filtrate concentrated under vacuum,
The residue was dissolved in EtOAc. The resulting solution was washed (brine), dried (Na ₂ SO ₄ ), filtered, concentrated in vacuo and the residue purified by flash chromatography (acetone: hexane (1: 1)). (33%) occurred; TLC, R _f = 0.40 and 0.44, MeOH: CHCl ₃ (1: 9).

The results of the analysis were as follows: C ₂₁ H ₃₀ F ₃ N ₃ O ₄ S: C, 52.82; H, 6.33; N, 8.80 Measured value: C, 52. 43; H, 6.53; N, 8.08 c. 3 (SR) -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide CrO ₃ (0..0) in anhydrous CH ₂ Cl ₂ (50 ml).
84 g, 8.4 mmol) in a suspension of anhydrous pyridine (1.
36 ml, 17 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The resulting wine-colored suspension had celite (C
elite) 1 g, followed by the product from Reference Example 6b (0.20 g, 0.42 m) in CH ₂ Cl ₂ (5 ml).
Mol) was added. The mixture was stirred until TLC showed all alcohol was consumed. The mixture was then filtered through a silica gel plug with methanol: chloroform (1: 9) and the solvent removed from the filtrate under vacuum. The crude product was purified by preparative TLC (MeOH: CHCl
Purification by ₃ (5:95)), the product as a white solid (150 mg) occurs; HPLC, t _R = 4.18
And 5.65, Col. A, H ₂ O: CH ₃ CN (60:
40), FR = 2.0.

The results of the analysis were as follows: C ₂₁ H ₂₈ F ₃ N ₃ O ₄ S.0.5H ₂ O: C, 52.06; H, 6.03; N, 8.67 Measurement Value: C, 52.03; H, 6.19; N, 8.38 Reference Example 7 a. 1-adamantansulfinyl chloride aluminium trichloride (40 g, 3 mol) and thionyl chloride (200
ml, 2.7 mol) and the mixture was cooled to -20 ° C. Adamantane was added in portions over 2 1/2 hours and the resulting mixture was stirred for 1 hour and allowed to warm to room temperature. After removing thionyl chloride under vacuum, the residue was diluted with CCl ₄ and the aluminum trichloride was decomposed with ice and water. The layers were separated, the organic layer was washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was distilled under vacuum (1 torr, 133.3 pascals) using a Vigro column to give the product (28.
8 g; boiling point 118-128 ° C.) was obtained; TLC, R _f =
0.6-0.4, EtOAc to hexane (15: 8
5).

Reference Example 8 3 (RS)-[2-methoxycarbonyl) ethylcarbonyl] -L-valyl-N- [3- (4-methyl-1,
1,1 trifluoromethyl-2-Okisopenchi Le)]
-L-prolinamide a. N-benzyloxycarbonyl-L-valyl-L-proline t-butyl ester DM
N-benzyloxycarbonyl-in F (565 ml)
L-valine (56.25 g, 0.244 mol) and H
A solution of OBT (60.67 g, 0.45 mol) was cooled to 5 ° C. DCC (50.89 g, 0.247 mol) was added in one portion. The mixture was stirred at 5 ° C. for an additional 15 minutes, then L-proline t-butyl ester (38.3
6 g, 0.224 mol) was added. The mixture was stirred at 5 ° C. for a further 2 hours and then at room temperature for 48 hours. The mixture was filtered and concentrated under vacuum. The oily residue was washed with EtOAc (1
It was dissolved in 1) and subsequently washed with 20% aqueous citric acid, saturated aqueous NaHCO ₃ and brine. The organic phase is Na ₂ S
Dry over O ₄ , filter, and concentrate under vacuum to give the product (92.0 g) as a white foam; TLC, R
_f = 0.9, silica gel, CHCl ₃ : EtOAc (8
5:15).

B. L-Valyl-L-proline t-butyl ester EtOH (11) product of Reference Example 8a (92.0 g, 0.227 mol) and 10% Pd / c.
The mixture of (10 g) was put on a pearl shaker for 6 hours and 4.2.
Hydrogenated at room temperature, Kg / cm ² (60 psi). The mixture was filtered through Celite and concentrated in vacuo to give the product (62g) as a viscous yellow oil; TL
C, R _f = 0.3, silica gel, MeOH: CHCl
₃ (10:90).

C. N- [2- (methoxycarbonyl) ethylcarbonyl] -L-valyl-L-proline-1,1
-Dimethyl ethyl ester 1N aqueous NaOH (8.m
l) was precooled (0 ° C.), CH ₂ Cl ₂ (60 m
was added to a solution of the product of Reference Example 8b (2.1 g, 7.8 mmol) in l). The mixture was stirred and 3-carbomethoxypropionyl chloride (0.96 ml, 7.8 m).
Mol) was added. The reaction mixture was vigorously stirred at 0 ° C. for 15 minutes. The solution was removed from the ice bath and H ₂ O (30 ml)
And diluted with 1N aqueous HCl. The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ . Combine the organic layers,
Dry over Na ₂ SO ₄ , filter, and concentrate under vacuum. The resulting residue is placed on a silica gel column with Et ₂ O, followed by Et.
Purification by flash chromatography, eluting with PAc gave the product (2.68 g); TLC, R _f.
= 0.28, silica gel, Et ₂ O.

D. N- [2- (methoxycarbonyl) ethylcarbonyl] -L-valyl-L-proline trifluoroacetic acid (11.0 ml, 143 mmol) was added to CH ₂ Cl _2.
The product of Reference Example 8c (2.68 g, in 11 ml)
6.98 mmol). The mixture was stirred for 4 hours and concentrated in vacuo to give the product (2.13g) used without further purification.

E. 2 (RS), 3 (SR)-[2- (methoxycarbonyl) ethylcarbonyl] -L-valyl-
N- [3- (4-methyl-1,1,1-trifluoro-
2-Hydroxy-pentyl)]-L-prolinamide isobutyl chloroformate (0.85 ml, 6.5 mmol) was pre-cooled (-15 ° C), THF (50 m).
l) N-methylmorpholine (0.71 ml, 6.5)
mmol) and the product of Reference Example 8d (2.13 g, 6.
5 mmol) of the solution. The reaction mixture was stirred for 10 minutes and the temperature was reduced to -50 ° C. THF (50 ml)
N-methylmorpholine (0.71 ml, 6.5 mmol) in and the product prepared using the method of Example 1c (1.
39 g, 6.5 mmol) was added in one portion and the reaction mixture was stirred overnight allowing it to warm to room temperature. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken up in EtOAc and washed successively with 1N aqueous HCl and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The resulting residue on silica gel, M
Flash chromatography-purification, eluting with MeOH: CHCl ₃ (5:95), gave the product (1.9
2 g) was obtained; TLC, R _f = 0.24, silica gel,
MeOH: CHCl ₃ (5:95).

F. 3 (RS)-[2- (methoxycarbonyl) ethylcarbonyl] -L-valyl-N- [3-
(4-Methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide CH ₂ Cl ₂ (12m
A solution of DNSO (11.2 ml, 0.158 mol) in 1) was gradually pre-cooled (-60 ° C), CH ₂ Cl _2.
Oxalyl chloride (6.9 ml, 0.
079 mol). CH ₂ Cl ₂ (160m
The product of Reference Example 8e in l) (1.90 g, 3.95 m)
Mol) solution was added to the reaction mixture and stirred at −60 ° C. for 1 hour. Diisopropylethylamine (28.0m
1, 0.158 mol) was added slowly, allowing the reaction mixture to warm to room temperature. The solution was treated with 1N aqueous HCl (2x
80 ml) and brine. The organic layer is Na ₂ S
Dry over O ₄ , filter and concentrate to give the crude product (3.5
g) was obtained. Filter the product through silica gel with EtOAc, followed by MeOH: CHCl on silica gel.
Flash chromatography using ₃ (5:95)
To give the product (1.49 g); TLC,
R _f = 0.31, silica gel, MeOH: CHCl
₃ (5:95); Characteristic ¹ H NMR shift (CD ₃ SOC
D ₃ , 250 MHz): 0.9, m, 12H; 3.5
4, s, 3H; 3.54-3.68, m, 2H; 4.3
4, m, 1H; 4.40, m, 1H; 4.48, dd,
1 / 2H; 4.58, dd, 1 / 2H; 8.1, d, 1
H; 8.58, dd, 1H.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 37/64 AED 8314-4C C07D 401/12 213 7602-4C 409/12 333 7602-4C C07K 5 / 08 8318-4H C12N 9/99 (72) Inventor John Anthony Schwartz United States Delaware Wilmington Concord Pike and New Murphy Road (No Address) (72) Inventor Andrew Show United States Delaware Wilmington Concord Pike and New Murphy Road (No house number) (72) Inventor Mark Morris Stein United States Delaware Wilmington Concord Pike and New Murphy Road ( (72) Inventor Diane Amy Trainer United States Delaware Wilmington Concord Pike and New Murphy Road (No Address) (72) Inventor Richard Alan Wildanger United States Delaware Wilmington Concord Pike and New Murphy Road (No Address) (72) Inventor Donald John Wollanin United States Delaware Wilmington Concord Pike and New Murphy Road (No Address)

Claims (12)

[Claims] 1. Formula I [In the formula, n is 1, R ¹ is an alkyl group having 1 to 5 carbon atoms, and A is —CO—, —NH—CO—, —
O-CO- or -S (O ₂₎ - a and, directly B bond or the formula: is ^{-NH · CHR 5 · CO · NH} · CHR 2 · CO- group, wherein R ² is phenyl, benzyl A group or may have benzyloxycarbonyl, benzyloxycarbonylamino, phenylsulfonylamino or (phenylsulfonylamino) carbonyl (C
1-4) an alkyl group, R ⁵ is a (C1-4) alkyl group which may have benzyloxycarbonyl or benzyloxycarbonylamino, and R ³ is the following: (1) (C1- 4) Alkoxy carbonyl, [(C1
~ 4) alkoxycarbonyl] amino, carboxy,
2-[(C1-4) alkoxy] ethoxy, adamantyl, morpholinyl, pyridyl, thienyl, oxopyrrolidinyl, phenyl, [(C1-4) alkoxycarbonyl] phenyl, (carboxy) phenyl, phenoxy, (acetamido) phenoxy , [(C1-4) alkoxycarbonyl] phenoxy, (carbamoylmethyl) phenoxy, benzenesulfonylamino, (methanesulfonylamino) carbonyl, (benzenesulfonylamino) carbonyl, (naphthalenesulfonylamino) carbonyl, (adamantanesulfonylamino) carbonyl Or
(Chlorobenzenesulfonylaminocarbonyl) (C1-6) alkyl group optionally having phenyl; (2) naphthyl, adamantyl, (amino) (chloro)
Phenyl group, hydroxy, (C1-4) alkoxy,
(C1-4) substituted with alkoxycarbonyl, carboxy, halogeno, dihalogeno, acetamide, (methanesulfonylamino) carbonyl, (naphthalenesulfonylamino) carbonyl or [N-benzyl- (4-bromobenzenesulfonyl) amino] carbonyl A good phenyl group; (3) a group of the formula W.SO ₂ .NH.CO.phenyl (where W is phenyl which may have halogeno or nitro); (4) a formula Y.CO.NH. A group of (CH ₂ ) _m − (where m
Is 2-5, Y is phenyl, benzyl, diphenylmethyl, phenoxymethyl, benzyloxy, (C1-
4) alkoxy, [(C1-4) alkoxycarbonyl] phenylamino, (2-pyridyl) ethoxy or carboxyphenylamino); (5) optionally substituted with (C1-4) alkoxycarbonyl or carboxy. Cyclopentyl or undecyl group; (6) 2-phenylvinyl group optionally substituted with (C1-4) alkoxycarbonyl, carbonyl or (chlorobenzenesulfonylamino) carbonyl in the phenyl ring; (7) 2- (ureidocarbonyl) Vinyl, di (benzyloxymethyl) methyl or di (2-phenoxyethyl) methyl group;] or a pharmaceutically acceptable acid or base addition salt thereof. 2. The following groups: 1) 3 (RS)-[2- (methoxycarbonyl) ethylcarbonyl] -L-norleucyl-L-valyl-N-.
[3- (4-methyl-1,1,1-trifluoro-2-
Oxopentyl)]-L-prolinamide, 2) 3 (RS)-[(phenylmethoxy) carbonyl]
-L-alpha-glutamyl-L-valyl-N- [3-
(4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide phenylmethyl ester, 3) 3 (RS) -N 2 - [2- ( methoxycarbonyl)
Ethylcarbonyl] -N ⁶ - [(phenylmethoxy) carbonyl] -L- lysyl -L- valyl -N- [3- (4
- methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide, 4) 3S (or R) -N ^2, N ⁶ - di [(phenylmethoxy) carbonyl] -L- lysyl -L-valyl-N- [3
- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide, 5) 3- (RS) -N 2, N 6 - di (phenylmethoxy carbonyl) -L- Lysyl-L-valyl-N- [3-
(1,1,1-Trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide, 6) 3- (RS)-[1,4-dioxo-4-[(tricyclo [3.3. .1.1 ^{3 '7]} deci-1-yl] sulfonylamino] butyl] -L- leucyl -L- valyl -N
-[3- (1,1,1-trifluoro-4-methyl-2
-Oxopentyl)]-L-prolinamide, compound according to claim 1. 3. The following groups: 1) 3 (RS)-[(2-carboxyethyl) carbonyl] -L-norleucyl-L-valyl-N- [3- (4.
- methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide, 2) 3 (RS) -N 2 - [(2- carboxyethyl) carbonyl] -N ⁶ - [(phenyl Methoxy) carbonyl] -L-lysyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide, 3) 3 (RS) -[1,4-Dioxo-4- (phenylsulfonylamino) butyl] -L-leucyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl) ] -L-prolinamide, 4) 3 (RS)-[4- (methylsulfonylamino)-
1,4-dioxobutyl] -L-leucyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide and 5) 3 ( RS) -N ² - [1,4-dioxo-4- (phenylsulfonylamino) - butyl] -N ⁶ - -L- phenylmethoxycarbonyl lysyl -L- valyl -N-
[3- (1,1,1-trifluoro-4-methyl-2-
A compound according to claim 2 selected from oxopentyl)]-L-prolinamide. 4. The acid addition salt is hydrochloric acid, hydrobromic acid, sulfuric acid,
The compound according to claim 1, which is formed by using nitric acid, citric acid, maleic acid, fumaric acid or acetic acid. 5. The base addition salt is an alkali metal hydroxide,
The compound according to claim 1, which is formed by using an alkali metal carbonate, an alkali metal bicarbonate, an alkaline earth metal hydroxide or an organic amine salt. 6. Formula I: embedded image [In the formula, n is 1, R ¹ is an alkyl group having 1 to 5 carbon atoms, and A is —CO—, —NH—CO—, —
O-CO- or -S (O ₂₎ - a and, directly B bond or the ^{formula: -NH · CHR 5 · CO ·} NH · CHR 2 · CO-
Wherein R ² is a phenyl, benzyl group or may have a benzyloxycarbonyl, benzyloxycarbonylamino, phenylsulfonylamino or (phenylsulfonylamino) carbonyl group (C1-4) Is an alkyl group, R ⁵ is a (C1-4) alkyl group optionally having benzyloxycarbonyl or benzyloxycarbonylamino, and R ³ is the following: (1) (C1-4) alkoxy. Carbonyl, [(C1
~ 4) alkoxycarbonyl] amino, carboxy,
2-[(C1-4) alkoxy] ethoxy, adamantyl, morpholinyl, pyridyl, thienyl, oxopyrrolidinyl, phenyl, [(C1-4) alkoxycarbonyl] phenyl, (carboxy) phenyl, phenoxy, (acetamido) phenoxy , [(C1-4) alkoxycarbonyl] phenoxy, (carbamoylmethyl) phenoxy, benzenesulfonylamino, (methanesulfonylamino) carbonyl, (benzenesulfonylamino) carbonyl, (naphthalenesulfonylamino) carbonyl, (adamantanesulfonylamino) carbonyl Or
(Chlorobenzenesulfonylaminocarbonyl) (C1-6) alkyl group optionally having phenyl; (2) naphthyl, adamantyl, (amino) (chloro)
Phenyl group, hydroxy, (C1-4) alkoxy,
(C1-4) substituted with alkoxycarbonyl, carboxy, halogeno, dihalogeno, acetamide, (methanesulfonylamino) carbonyl, (naphthalenesulfonylamino) carbonyl or [N-benzyl- (4-bromobenzenesulfonyl) amino] carbonyl A good phenyl group; (3) a group of the formula W.SO ₂ .NH.CO.phenyl (where W is phenyl which may have halogeno or nitro); (4) a formula Y.CO.NH. A group of (CH ₂ ) _m − (where m
Is 2-5, Y is phenyl, benzyl, diphenylmethyl, phenoxymethyl, benzyloxy, (C1-
4) alkoxy, [(C1-4) alkoxycarbonyl] phenylamino, (2-pyridyl) ethoxy or carboxyphenylamino); (5) optionally substituted with (C1-4) alkoxycarbonyl or carboxy. A cyclopentyl or undecyl group; (6) 2-phenylvinyl optionally substituted with (C1-4) alkoxycarbonyl, carbonyl or (chlorobenzenesulfonylamino) carbonyl in the phenyl ring; (7) 2- (ureidocarbonyl) vinyl A di (benzyloxymethyl) methyl or di (2-phenoxyethyl) methyl group;] or a pharmaceutically acceptable acid or base addition salt thereof, [Chemical 3] Trifluoromethylketone-substituted peptide derivative characterized by oxidizing a compound of the formula: wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A and n are as described above. Manufacturing method. 7. (a) Oxalyl chloride, dimethyl sulfoxide and tertiary amine in methylene chloride (b) acetic anhydride and dimethyl sulfoxide, (c) chromium trioxide-pyridine complex in methylene chloride and (d) in methylene chloride. 7. The method according to claim 6, wherein the oxidation is carried out using a member selected from the group consisting of Dess-Martin periodinane of. 8. A process according to claim 7, wherein the oxidation is carried out with Dess-Martin periodinane in methylene chloride. 9. Formula I: embedded image [In the formula, n is 1, R ¹ is an alkyl group having 1 to 5 carbon atoms, and A is —CO—, —NH—CO—, —
O-CO- or -S (O ₂₎ - a and, directly B bond or the ^{formula: -NH · CHR 5 · CO ·} NH · CHR 2 · CO-
Wherein R ² is a phenyl, benzyl group or may have a benzyloxycarbonyl, benzyloxycarbonylamino, phenylsulfonylamino or (phenylsulfonylamino) carbonyl group (C1-4) Is an alkyl group, R ⁵ is a (C1-4) alkyl group optionally having benzyloxycarbonyl or benzyloxycarbonylamino, and R ³ is the following: (1) carboxy or (carboxy) phenyl (C1-6) alkyl group having; (2) phenyl group substituted with carboxy; (3) cyclopentyl or undecyl substituted with carboxy; (4) 2-phenyl substituted with carboxy in the phenyl ring. Selected from vinyl;] or a pharmaceutically acceptable compound thereof To prepare acid or base addition salts, a compound of formula VIIa or VIIc: [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A and n are as defined above, wherein R ³ is a (C1-6) alkyl having a (C1-4) alkoxycarbonyl group. , Phenyl, cyclopentyl or 2-phenylvinyl group or [(C1-
4) Having an alkoxycarbonylphenyl (C1-
6) Alkyl group] is oxidized to convert a carboxylic acid ester group into a corresponding carboxy group, and a process for producing a peptide derivative substituted with trifluoromethylketone. 10. Formula I: [In the formula, n is 1, R ¹ is an alkyl group having 1 to 5 carbon atoms, and A is —CO—, —NH—CO—, —
O-CO- or -S (O ₂₎ - a and, directly B bond or the formula: is ^{-NH · CHR 5 · CO · NH} · CHR 2 · CO- group, wherein R ² is phenyl, benzyl A group or a (C1-4) alkyl group which may have a benzyloxycarbonyl, benzyloxycarbonylamino, phenylsulfonylamino or (phenylsulfonylamino) carbonyl group, and R ⁵ is benzyloxycarbonyl or benzyl. It is a (C1-4) alkyl group optionally having oxycarbonylamino, and R ³ is the following: (1) benzenesulfonylamino, (methanesulfonylamino) carbonyl, (benzenesulfonylamino) carbonyl, (naphthalene) Sulfonylamino) carbonyl,
(C1-6) alkyl group having (adamantanesulfonylamino) carbonyl or (chlorobenzenesulfonylaminocarbonyl) phenyl; (2) (methanesulfonylamino) carbonyl, (naphthalenesulfonylamino) carbonyl or [N-benzyl- (4-bromo A phenyl group substituted with benzenesulfonyl) amino] carbonyl; (3) a group of the formula W.SO ₂ .NH.CO.phenyl (where W is phenyl which may have halogeno or nitro); 4) selected from 2-phenylvinyl substituted with (chlorobenzenesulfonylamino) carbonyl in the phenyl ring] or a pharmaceutically acceptable acid or base addition salt thereof. Formula VIIa or VIIc: [Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , A and n are as defined above, and R ³ is a (C1-6) alkyl having a carboxylic acid group, phenyl, cyclopentyl or 2-phenyl. Having a vinyl group or a (carboxy) phenyl group (C1-
6) It is an alkyl group], and the carboxylic acid group is coupled to the amino group of a suitable sulfonamide to produce a trifluoromethylketone-substituted peptide derivative. 11. The coupling method is (a) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride in methylene chloride and 4-dimethylaminopyridine (b) 1,3-dicyclohexyl in methylene chloride. 11. The method according to claim 10, carried out with one from the group consisting of carbodiimide and 4-dimethylaminopyridine. 12. Formula I: embedded image [In the formula, n is 1, R ¹ is an alkyl group having 1 to 5 carbon atoms, and A is —CO—, —NH—CO—, —
O-CO- or -S (O ₂₎ - a and, directly B bond or the formula: is ^{-NH · CHR 5 · CO · NH} · CHR 2 · CO- group, wherein R ² is phenyl, benzyl A group or a (C1-4) alkyl group which may have a benzyloxycarbonyl, benzyloxycarbonylamino, phenylsulfonylamino or (phenylsulfonylamino) carbonyl group, and R ⁵ is benzyloxycarbonyl or benzyl. It is a (C1-4) alkyl group optionally having oxycarbonylamino, and R ³ is the following: (1) (C1-4) alkoxycarbonyl, [(C1
~ 4) alkoxycarbonyl] amino, carboxy,
2-[(C1-4) alkoxy] ethoxy, adamantyl, morpholinyl, pyridyl, thienyl, oxopyrrolidinyl, phenyl, [(C1-4) alkoxycarbonyl] phenyl, (carboxy) phenyl, phenoxy, (acetamido) phenoxy , [(C1-4) alkoxycarbonyl] phenoxy, (carbamoylmethyl) phenoxy, benzenesulfonylamino, (methanesulfonylamino) carbonyl, (benzenesulfonylamino) carbonyl, (naphthalenesulfonylamino) carbonyl, (adamantanesulfonylamino) carbonyl Or
(Chlorobenzenesulfonylaminocarbonyl) (C1-6) alkyl group optionally having phenyl; (2) naphthyl, adamantyl, (amino) (chloro)
Phenyl group, hydroxy, (C1-4) alkoxy,
(C1-4) substituted with alkoxycarbonyl, carboxy, halogeno, dihalogeno, acetamide, (methanesulfonylamino) carbonyl, (naphthalenesulfonylamino) carbonyl or [N-benzyl- (4-bromobenzenesulfonyl) amino] carbonyl A good phenyl group; (3) a group of the formula W.SO ₂ .NH.CO.phenyl (where W is phenyl which may have halogeno or nitro); (4) a formula Y.CO.NH. A group of (CH ₂ ) _m − (where m
Is 2-5, Y is phenyl, benzyl, diphenylmethyl, phenoxymethyl, benzyloxy, (C1-
4) alkoxy, [(C1-4) alkoxycarbonyl] phenylamino, (2-pyridyl) ethoxy or carboxyphenylamino); (5) optionally substituted with (C1-4) alkoxycarbonyl or carboxy. A cyclopentyl or undecyl group; (6) 2-phenylvinyl optionally substituted with (C1-4) alkoxycarbonyl, carbonyl or (chlorobenzenesulfonylamino) carbonyl in the phenyl ring; (7) 2- (ureidocarbonyl) vinyl , A di (benzyloxymethyl) methyl or di (2-phenoxyethyl) methyl group; or a pharmacologically acceptable acid or base addition salt thereof which is harmless Elastase Mediation Containing with a Pharmaceutically Acceptable Diluent or Carrier Therapeutic agent for woven degeneration diseases.